# ent

id: cord-269151-r426u5dz
type: PROTEIN
entity:
  AT1 angiotensin II receptor type 1 AT2 angiotensin II receptor type 2 ACE2 angiotensin converting enzyme 2


id: cord-269151-r426u5dz
type: GGP
entity:
  angiotensin receptor blockers ACEI angiotensin converting enzyme inhibitor ARB angiotensin receptor blocker AT1 angiotensin II receptor type 1 AT2 angiotensin II receptor type 2 ACE2 angiotensin converting enzyme 2


id: cord-269151-r426u5dz
type: ORG
entity:
  the American College of Cardiology American Heart Association Task Force on Clinical Practice Guidelines


id: cord-269151-r426u5dz
type: ORG
entity:
  the American College of Cardiology American Heart Association Task Force on Clinical Practice Guidelines Cough


id: cord-001773-mqk0sx5n
type: DNA
entity:
  HindIII and KpnI restriction sites Scrambled Silencer Negative Control no 1 small interfering RNA siRNA


id: cord-002307-gk84fnb9
type: GGP
entity:
  insoluble amyloid β Aβ load r 0 199 P 0 059 and p tau load r 0 252 P 0 05 e Bar chart showing a trend towards increased ACE 1 ACE 2


id: cord-002307-gk84fnb9
type: GGP
entity:
  Alzheimer s disease vascular dementia and other dementias Prevention of dementia in randomised double blind placebo controlled Systolic Hypertension


id: cord-002307-gk84fnb9
type: CHEMICAL
entity:
  ACE 1 4 We speculate that the sequential cleavage of Aβ 43 first by ACE 2 and the subsequent cleavage of Aβ 42 to Aβ 40 the


id: cord-002468-onpmkjaz
type: PROTEIN
entity:
  actin A1978 1 4000 Sigma Madrid Spain or mouse monoclonal anti tubulin T5168 1 10000 Sigma Densitometric


id: cord-298515-5n7hxhbg
type: PROTEIN
entity:
  HRP conjugated goat anti rabbit secondary antibody 1 10 000 dilution Santa Cruz Biotechnology Santa Cruz CA


id: cord-005386-p37rw8dh
type: PROTEIN
entity:
  Angiotensin converting enzyme I D angiotensinogen T174M M235T and angiotensin II type 1 receptor A1166C gene polymorphisms


id: cord-264828-6w13xo2a
type: ORG
entity:
  Mario Milco D Elios Department of Experimental and Clinical Medicine University of Florence Florence Italy


id: cord-018009-8j40876m
type: ORG
entity:
  the American College of Cardiology American Heart Association Task Force on Practice Guidelines Committee


id: cord-289477-cjm7qhr4
type: PROTEIN
entity:
  bradykinin potentiating nonapeptide BPP 9α date 2005 04 25 journal Peptides DOI 10 1016 j peptides 2005 03 046 sha c74d7b08b90e1af07e6b74ba468564db3073dc01 doc_id 289477 cord_uid cjm7qhr4


id: cord-016742-y7jgjera
type: PROTEIN
entity:
  angiotensin converting enzyme inhibitors angiotensin II receptor blockers aldosterone antagonists beta blockers


id: cord-016742-y7jgjera
type: GGP
entity:
  diuretics beta blockers ACE inhibitors ARBs aldosterone antagonists 5 Post myocardial infarction beta blockers ACE inhibitors aldosterone


id: cord-016742-y7jgjera
type: GGP
entity:
  diuretics beta blockers ACE inhibitors CCBs 5 Diabetes Diuretics beta blockers ACE inhibitors ARBs CCBs 5


id: cord-016742-y7jgjera
type: ORG
entity:
  the Joint National Committee on Prevention Detection Evaluation and Treatment of High Blood Pressure


id: cord-016742-y7jgjera
type: DISEASE
entity:
  impaired left ventricular systolic reduced ejection fraction or diastolic preserved ejection fraction function


id: cord-266289-dkxhbmic
type: CHEMICAL
entity:
  N terminal Fig 1 Schematic representation of the domain structures of sACE and tACE sACE consists of two homologous domains the N and C domains Both


id: cord-253862-jl1zhg13
type: TAXON
entity:
  human coronavirus OC43 HCoV OC43 human coronavirus HKU1 HCoV HKU1 Human coronavirus 229E HCoV 229E human coronavirus


id: cord-253862-jl1zhg13
type: DISEASE
entity:
  human coronavirus OC43 HCoV OC43 human coronavirus HKU1 HCoV HKU1 Human coronavirus 229E HCoV 229E human coronavirus NL63 HCoV NL63


id: cord-317878-bqpj0ey0
type: DISEASE
entity:
  acute respiratory distress syndrome Acute respiratory distress syndrome Acute respiratory distress syndrome


id: cord-266755-y2lf7ssp
type: DNA
entity:
  2019 novel coronavirus 2019 nCoV later renamed severe acute respiratory syndrome coronavirus 2 SARSCoV 2


id: cord-306739-4lokd97u
type: CHEMICAL
entity:
  zu nutzen Eine Pilotstudie zu einer lungenprotektiven Therapie mit ACE Hemmern bei mechanisch beatmeten Patienten mit ARDS


id: cord-319022-1twsxzcd
type: WORK_OF_ART
entity:
  Neuroscience Diverse Roles of Angiotensin Receptor Intracellular Signaling Pathways in the Control of Water and Salt Intake


id: cord-319022-1twsxzcd
type: ORG
entity:
  Indication Timing and Surgical Treatment of Spontaneous Intracerebral Hemorrhage Systematic Review and Proposal of a Management Algorithm Risk Factors


id: cord-005927-a9sj00y8
type: DNA
entity:
  primer pairs 5 TGAATTCCACCATGGGCCAAGGTTGGGCTACTCCAGG 3 and 5 GAATTCGTCACTTATCATCATCATCCTTATAATCCTGCTGTGGCTCCAG GTACAGGC 3


id: cord-005927-a9sj00y8
type: DNA
entity:
  5 CTTGGTGATAGCGCACCACGATATGGGCC ACATCCAGTATTTCATGCA 3 and 5 CATGGAGGACTTGGTGATAGCGC ACAAGGAAATGGGCAAGATCCAGT ATTTCATGC 3


id: cord-351567-ifoe8x28
type: WORK_OF_ART
entity:
  Camostat Mesilate Pancrelipase and Rabeprazole Combination Therapy Improves Epigastric Pain in Early Chronic Pancreatitis


id: cord-342786-dl8vjwfn
type: PROTEIN
entity:
  TLR4 transmembrane lipopolysaccharide receptor 4 ICAM intercellular adhesion molecule VCAM vascular cell adhesion molecule NF κB nuclear factor kappa light chain enhancer


id: cord-342786-dl8vjwfn
type: PROTEIN
entity:
  Neprilysin B receptor NPR A B Neprilysin receptor A B HDAC Histone Deacetylase GATA Globin transcription factor NFAT Nuclear factor of activated T cells PPAR


id: cord-342786-dl8vjwfn
type: GGP
entity:
  Angiotensin 1 7 ACE Angiotensin Converting Enzyme AT1R Angiotensin II receptor type 1 AT2R Angiotensin II receptor type 2 Natriuretic peptide receptor A B guanylate cyclase


id: cord-342786-dl8vjwfn
type: GGP
entity:
  protein kinase II CAM Calmodulin cGMP Cyclic guanosine monophosphate Atrial Brain natriuretic peptide TLR4 transmembrane lipopolysaccharide receptor 4 ICAM intercellular adhesion molecule VCAM vascular cell adhesion molecule NF κB nuclear factor kappa light chain enhancer


id: cord-342786-dl8vjwfn
type: WORK_OF_ART
entity:
  Shared Features of Endothelial Dysfunction between Sepsis and Its Preceding Risk Factors Aging and Chronic Disease Neutrophils


id: cord-342786-dl8vjwfn
type: ORG
entity:
  Sichuan Provincial People s Hospital Antiplatelet Therapy After Percutaneous Coronary Intervention in Patients With COVID 19


id: cord-342786-dl8vjwfn
type: DISEASE
entity:
  myocardial injury myocardial infarction arrhythmias heart failure cardiomyopathy shock thromboembolism


id: cord-334490-42gykxdx
type: CELL_LINE
entity:
  ESC COVID 19 Guidance A Novel Coronavirus from Patients with Pneumonia in China Clinical Characteristics of Coronavirus Disease 2019


id: cord-334490-42gykxdx
type: PRODUCT
entity:
  A A Kammerlander MD PhD ao Univ Prof Dr J Mascherbauer Division of Cardiology Department of Medicine II Medical University


id: cord-302316-raf5rlkq
type: DISEASE
entity:
  coronary artery disease congestive heart failure cardiac arrhythmia chronic obstructive pulmonary disease


id: cord-349445-yh6ndtgm
type: PROTEIN
entity:
  Transforming Growth Factor β1 Induced Endothelial To Mesenchymal Transition and Tissue Fibrosis by Endothelin 1 ET 1 A


id: cord-349445-yh6ndtgm
type: PROTEIN
entity:
  Angiotensin Converting Enzyme 2 Angiogenesis 1 7 Mas Axis Confers Cardiopulmonary Protection against Lung Fibrosis and Pulmonary Hypertension


id: cord-349445-yh6ndtgm
type: GGP
entity:
  ACE 2 Angiotensin converting enzyme 2 Ang 1 7 Angiotensin AT 1 Angiotensin II type 1 receptor ET 1 Endothelin 1 fMLP


id: cord-349445-yh6ndtgm
type: ORG
entity:
  Interleukin 6 Induces Oxidative Stress and Endothelial Dysfunction by Overexpression of the Angiotensin II Type 1 Receptor Endothelium


id: cord-349445-yh6ndtgm
type: ORG
entity:
  Structural Substrate Conditions Required for Neutral Endopeptidase Mediated Natriuretic Peptide Degradation


id: cord-349445-yh6ndtgm
type: LAW
entity:
  ARNIs COVID 19 Treatment Close to a Cure A Rapid Review of Pharmacotherapies for the Novel Coronavirus Risks Related to the Use of Non Steroidal Anti Inflammatory Drugs in Community Acquired Pneumonia in Adult and Pediatric Patients


id: cord-015859-5kt59ose
type: PROTEIN
entity:
  phospholipase A 2 arachidonic acid pathway the phospholipase D phosphatidylcholine phosphatidic acid pathway and tyrosine kinases


id: cord-015859-5kt59ose
type: CHEMICAL
entity:
  ACE gene is located on chromosome 17 Somatic ACE has 2 homologous domains which share 60 sequence homology Both domains contain a catalytically active site Wei et al 1991a and are situated at the N and C terminal side of ACE According to their position


id: cord-306755-9q1mawfs
type: DNA
entity:
  gamma X citri gi 21241971 gi 21107345 Xanthomonas oryzae gi 37931607 gi 58583162 Xanthomonas campestris


id: cord-306755-9q1mawfs
type: CHEMICAL
entity:
  gi 37931607 gi 58583162 Xanthomonas campestris pv campestris gi 21230574 gi 21112152 Shewanella oneidensis gi 24374038 gi 24348510 proteobacteria


id: cord-306755-9q1mawfs
type: CHEMICAL
entity:
  angiotensinconverting enzyme angiotensin 1 7 and keto ACE The PyMOL Molecular Graphics System Environmental


id: cord-338417-7kw9lws0
type: GGP
entity:
  Syndr DOI 10 1016 j dsx 2020 03 016 sha 2d9c728274237f4eb1cce5faf8821b8f04d6dace doc_id 338417 cord_uid 7kw9lws0 BACKGROUND AND AIMS COVID 19


id: cord-338417-7kw9lws0
type: ORG
entity:
  The Canadian Cardiovascular Society UK Renal Association the International Society of Hypertension and European Society of Hypertension


id: cord-006082-x1kankxd
type: GGP
entity:
  Rev Endocrinol DOI 10 1038 nrendo 2015 6 sha 3daed4a814faa5983f3582e85905d19ae0bb1a0d doc_id 6082 cord_uid x1kankxd The renin angiotensin aldosterone


id: cord-006082-x1kankxd
type: GGP
entity:
  mineralocorticoid receptor Abbreviations ACE angiotensin converting enzyme ACE2 angiotensin converting enzyme 2 Ang angiotensin ARB angiotensin receptor blocker ARN angiotensin receptor neprilysin AT1 type 1 Ang II receptor AT2 type 2 Ang II receptor IRAP leucyl cystinyl aminopeptidase


id: cord-006082-x1kankxd
type: GGP
entity:
  AT1 type 1 angiotensin II receptor AT2 type 2 angiotensin II receptor IRAP leucyl cystinyl aminopeptidase


id: cord-006082-x1kankxd
type: GGP
entity:
  ACE angiotensin converting enzyme ACE2 angiotensin converting enzyme 2 Ang angiotensin ARB angiotensin receptor blocker


id: cord-006082-x1kankxd
type: GGP
entity:
  angiotensin receptorneprilysin AT1 type 1 angiotensin II receptor AT2 type 2 angiotensin II receptor IRAP leucyl cystinyl aminopeptidase


id: cord-318327-9sh2eksm
type: CELL_LINE
entity:
  rat brush border epithelial cells lamina propria muscularis mucosa submucosal blood vessels and muscularis propria 77 Angiotensinogen mRNA


id: cord-318327-9sh2eksm
type: GGP
entity:
  endopeptidase Am aminopeptidase AT1R angiotensin type 1 receptor AT2R angiotensin type 2 receptor AT4R angiotensin type 4 receptor PRR pro renin receptor water


id: cord-290148-6cxndab8
type: GGP
entity:
  ACE 1 angiotensin converting enzyme 1 ACE 2 angiotensin converting enzyme 2 ACEIs angiotensin converting enyzme inhibitors ARBs angiotensin AT 1 receptor blockers AT 1 R angiotensin II type 1 receptor AT 2 R angiotensin II type 2 receptor NEP


id: cord-290148-6cxndab8
type: CHEMICAL
entity:
  ACE 1 Ang II AT 1 R axis while enhancing the ACE 1 Ang II AT 2 R the ACE 2 Ang 1 7 AT 2 R or the ACE 2 Ang 1 7 MasR receptor axes Figure 1 panel B


id: cord-290148-6cxndab8
type: CHEMICAL
entity:
  ACE 1 Ang II AT 1 R and the ACE 1 Ang II AT 2 R and the ACE 2 Ang 1 7 AT 2 R and the ACE 2 Ang 1 7 MasR


id: cord-277766-rxmpi61o
type: CHEBI
entity:
  l angiotensine 2 angiotensine 1 MAS l AC2 contrebalance l effet vasoconstricteur prolifératif fibrosant et pro inflammatoire


id: cord-277766-rxmpi61o
type: CHEMICAL
entity:
  tetrapeptide N acetyl Ser Asp Lys Pro on the G1 S transition of rat hepatocytes The tetrapeptide AcSDKP


id: cord-277766-rxmpi61o
type: CHEMICAL
entity:
  angiotensinconverting enzyme 2 ACE2 gene polymorphisms with parameters of left ventricular hypertrophy


id: cord-295041-5vpawtef
type: PROTEIN
entity:
  granulocyte colony stimulating factor granulocyte monocyte colony stimulating factor C X C motif chemokine ligand


id: cord-326820-11sl17ap
type: FAC
entity:
  angiotensin converting enzyme inhibitory peptides Association of angiotensin converting enzyme insertion


id: cord-311099-59pnm4fn
type: CHEMICAL
entity:
  angiotensin 1 7 metabolism in pulmonary and renal tissues Angiotensin 1 7 reduces bile duct proliferation and hepatic fibrosis


id: cord-301546-yck1t3pp
type: GGP
entity:
  Salmonella typhimurium Escherichia coli tapeworms avian leucosis virus turkey coronavirus turkey enterovirus Avincini


id: cord-286638-bqxyb61p
type: GGP
entity:
  Syndr DOI 10 1016 j dsx 2020 04 004 sha d1b9db2e6b0ff1103d594eacec6c46e7896bae56 doc_id 286638 cord_uid bqxyb61p BACKGROUND AND AIMS High


id: cord-286638-bqxyb61p
type: DISEASE
entity:
  chronic lower respiratory diseases HR 0 30 95 CI 0 10 to 0 93 even after the adjustment for multiple confounding factors


id: cord-352230-8mazd3eu
type: DISEASE
entity:
  HIV 1 infection Tripterygium wilfordii 197 Bakuchiol phenolic isoprenoid Psoralea corylifolia L 199 Rupestonic acid sesquiterpene Artemisia rupestris L


id: cord-352230-8mazd3eu
type: CHEMICAL
entity:
  nelfinavir lopinavir kaempferol quercetin luteolin 7glucoside demethoxycurcumin naringenin apigenin 7 glucoside oleuropein curcumin catechin epicatechin gallate zingerol gingerol


id: cord-286825-bu7j7kdr
type: PROTEIN
entity:
  Angiotensin converting enzyme ACE dipeptidyl carboxypeptidase I DCP I peptidase P carboxycathepsin peptidyl dipeptidase A


id: cord-286825-bu7j7kdr
type: PROTEIN
entity:
  Drosophila melanogaster Peptidyl dipeptidase A Angiotensin Iconverting enzyme Angiotensinconverting enzyme 2


id: cord-286825-bu7j7kdr
type: GGP
entity:
  Angiotensin converting enzyme ACE dipeptidyl carboxypeptidase I DCP I peptidase P carboxycathepsin peptidyl dipeptidase A peptidyl dipeptidase I kininase II EC 3 4 15 1


id: cord-259933-ggx4v0bz
type: ORG
entity:
  the Chinese Preventive Medicine Association Korean Society for Antimicrobial Therapy Korean Society for Healthcare associated Infection Control and Prevention Clinical


id: cord-269776-hj1s3ipp
type: CL
entity:
  follicle stimulating hormone progesterone estradiol testosterone prolactin and sex hormone binding globulin SHBG


id: cord-269776-hj1s3ipp
type: CHEMICAL
entity:
  C1 inhibitor gene of a patient with type I hereditary angioneurotic edema Nonsense mutations affect C1 inhibitor


# bib

id: cord-001773-mqk0sx5n
author: Lo, Chao-Sheng
date: 2015-08-01
txt: ./txt/cord-001773-mqk0sx5n.txt
cache: ./cache/cord-001773-mqk0sx5n.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4572079/
doi: 10.1007/s00125-015-3700-y
summary:
  AIMS/HYPOTHESIS: We investigated whether heterogeneous nuclear ribonucleoprotein F (hnRNP F) stimulates renal ACE-2 expression and prevents TGF-β1 signalling, TGF-β1 inhibition of Ace-2 gene expression and induction of tubulo-fibrosis in an Akita mouse model of type 1 diabetes. RESULTS: Overexpression of hnRNP F attenuated systemic hypertension, glomerular filtration rate, albumin/creatinine ratio, urinary angiotensinogen (AGT) and angiotensin (Ang) II levels, renal fibrosis and profibrotic gene (Agt, Tgf-β1, TGF-β receptor II [Tgf-βrII]) expression, stimulated anti-profibrotic gene (Ace-2 and Ang 1–7 receptor [MasR]) expression, and normalised urinary Ang 1–7 level in Akita Hnrnpf-Tg mice as compared with Akita mice. We reported that insulin inhibits high glucose stimulation of rat renal Agt gene expression via two nuclear proteins-heterogeneous nuclear ribonucleoproteins F and K (hnRNP F, hnRNP K)-that interact with the insulin-responsive element (IRE) in the Agt gene promoter [25] [26] [27] [28] , and that hnRNP F overexpression in RPTCs inhibits Agt gene expression and kidney hypertrophy in Akita Hnrnpf-Tg mice [29] .

title:
  Overexpression of heterogeneous nuclear ribonucleoprotein F stimulates renal Ace-2 gene expression and prevents TGF-β1-induced kidney injury in a mouse model of diabetes

abstract:
  AIMS/HYPOTHESIS: We investigated whether heterogeneous nuclear ribonucleoprotein F (hnRNP F) stimulates renal ACE-2 expression and prevents TGF-β1 signalling, TGF-β1 inhibition of Ace-2 gene expression and induction of tubulo-fibrosis in an Akita mouse model of type 1 diabetes. METHODS: Adult male Akita transgenic (Tg) mice overexpressing specifically hnRNP F in their renal proximal tubular cells (RPTCs) were studied. Non-Akita littermates and Akita mice served as controls. Immortalised rat RPTCs stably transfected with plasmid containing either rat Hnrnpf cDNA or rat Ace-2 gene promoter were also studied. RESULTS: Overexpression of hnRNP F attenuated systemic hypertension, glomerular filtration rate, albumin/creatinine ratio, urinary angiotensinogen (AGT) and angiotensin (Ang) II levels, renal fibrosis and profibrotic gene (Agt, Tgf-β1, TGF-β receptor II [Tgf-βrII]) expression, stimulated anti-profibrotic gene (Ace-2 and Ang 1–7 receptor [MasR]) expression, and normalised urinary Ang 1–7 level in Akita Hnrnpf-Tg mice as compared with Akita mice. In vitro, hnRNP F overexpression stimulated Ace-2 gene promoter activity, mRNA and protein expression, and attenuated Agt, Tgf-β1 and Tgf-βrII gene expression. Furthermore, hnRNP F overexpression prevented TGF-β1 signalling and TGF-β1 inhibition of Ace-2 gene expression. CONCLUSIONS/INTERPRETATION: These data demonstrate that hnRNP F stimulates Ace-2 gene transcription, prevents TGF-β1 inhibition of Ace-2 gene transcription and induction of kidney injury in diabetes. HnRNP F may be a potential target for treating hypertension and renal fibrosis in diabetes. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s00125-015-3700-y) contains peer-reviewed but unedited supplementary material, which is available to authorised users.


id: cord-002307-gk84fnb9
author: Kehoe, Patrick Gavin
date: 2016-11-25
txt: ./txt/cord-002307-gk84fnb9.txt
cache: ./cache/cord-002307-gk84fnb9.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5123239/
doi: 10.1186/s13195-016-0217-7
summary:
  METHODS: We measured ACE-2 activity by fluorogenic peptide substrate assay in mid-frontal cortex (Brodmann area 9) in a cohort of AD (n = 90) and age-matched non-demented controls (n = 59) for which we have previous data on ACE-1 activity, amyloid β (Aβ) level and tau pathology, as well as known ACE1 (rs1799752) indel polymorphism, apolipoprotein E (APOE) genotype, and cerebral amyloid angiopathy severity scores. ACE-2 enzyme activity is reduced in Alzheimer''s disease in association with increasing Aβ load and tau pathology ACE-2 activity was significantly reduced by approximately 50% in the mid-frontal cortex in AD compared with age-matched controls (P < 0.0001) (Fig. 1a) . Together, these data strongly suggest that reduced ACEFig. 2 Angiotensin-converting enzyme 2 (ACE-2) activity is reduced in association with apolipoprotein E (APOE) ε4 and ACE1 (rs1799752) indel polymorphism and increased in cerebral amyloid angiopathy (CAA).

title:
  Angiotensin-converting enzyme 2 is reduced in Alzheimer’s disease in association with increasing amyloid-β and tau pathology

abstract:
  BACKGROUND: Hyperactivity of the classical axis of the renin-angiotensin system (RAS), mediated by angiotensin II (Ang II) activation of the angiotensin II type 1 receptor (AT1R), is implicated in the pathogenesis of Alzheimer’s disease (AD). Angiotensin-converting enzyme-2 (ACE-2) degrades Ang II to angiotensin 1–7 (Ang ﻿﻿(1-7)) and counter-regulates the classical axis of RAS. We have investigated the expression and distribution of ACE-2 in post-mortem human brain tissue in relation to AD pathology and classical RAS axis activity. METHODS: We measured ACE-2 activity by fluorogenic peptide substrate assay in mid-frontal cortex (Brodmann area 9) in a cohort of AD (n = 90) and age-matched non-demented controls (n = 59) for which we have previous data on ACE-1 activity, amyloid β (Aβ) level and tau pathology, as well as known ACE1 (rs1799752) indel polymorphism, apolipoprotein E (APOE) genotype, and cerebral amyloid angiopathy severity scores. RESULTS: ACE-2 activity was significantly reduced in AD compared with age-matched controls (P < 0.0001) and correlated inversely with levels of Aβ (r = −0.267, P < 0.001) and phosphorylated tau (p-tau) pathology (r = −0.327, P < 0.01). ACE-2 was reduced in individuals possessing an APOE ε4 allele (P < 0.05) and was associated with ACE1 indel polymorphism (P < 0.05), with lower ACE-2 activity in individuals homozygous for the ACE1 insertion AD risk allele. ACE-2 activity correlated inversely with ACE-1 activity (r = −0.453, P < 0.0001), and the ratio of ACE-1 to ACE-2 was significantly elevated in AD (P < 0.0001). Finally, we show that the ratio of Ang II to Ang (1–7) (a proxy measure of ACE-2 activity indicating conversion of Ang II to Ang (1–7)) is reduced in AD. CONCLUSIONS: Together, our findings indicate that ACE-2 activity is reduced in AD and is an important regulator of the central classical ACE-1/Ang II/AT1R axis of RAS, and also that dysregulation of this pathway likely plays a significant role in the pathogenesis of AD. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s13195-016-0217-7) contains supplementary material, which is available to authorized users.


id: cord-002468-onpmkjaz
title: Characterization of ACE and ACE2 Expression within Different Organs of the NOD Mouse
author: Roca-Ho, Heleia
date: 2017-03-05
txt: ./txt/cord-002468-onpmkjaz.txt
cache: ./cache/cord-002468-onpmkjaz.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5372579/
doi: 10.3390/ijms18030563
summary:
  In this sense, since local RAS has been described, the aim of this study is to characterize angiotensin converting enzyme (ACE) and ACE2 activities, as well as protein expression, in several tissues of the non-obese diabetic (NOD) mice model. At cardiac level, there was a In serum samples, there was a significant increase of ACE2 activity in DB mice at early and late stages of diabetes as compared to CONT (p = 0.0003 and p = 0.0003, respectively) and insulin administration significantly decreased ACE2 activity in DB mice at early and late stages (p = 0.001 and p = 0.001, respectively) ( Figure 4a ). At cardiac level, there was a significant increase of ACE2 activity in DB mice in both early and late stages of DB as compared to CONT mice (p = 0.011 and p = 0.029, respectively), however, insulin administration did not modify this pattern (p = NS) (Figure 4b) .

abstract:
  Renin angiotensin system (RAS) is known to play a key role in several diseases such as diabetes, and renal and cardiovascular pathologies. Its blockade has been demonstrated to delay chronic kidney disease progression and cardiovascular damage in diabetic patients. In this sense, since local RAS has been described, the aim of this study is to characterize angiotensin converting enzyme (ACE) and ACE2 activities, as well as protein expression, in several tissues of the non-obese diabetic (NOD) mice model. After 21 or 40 days of diabetes onset, mouse serums and tissues were analyzed for ACE and ACE2 enzyme activities and protein expression. ACE and ACE2 enzyme activities were detected in different tissues. Their expressions vary depending on the studied tissue. Thus, whereas ACE activity was highly expressed in lungs, ACE2 activity was highly expressed in pancreas among the studied tissues. Interestingly, we also observed that diabetes up-regulates ACE mainly in serum, lung, heart, and liver, and ACE2 mainly in serum, liver, and pancreas. In conclusion, we found a marked serum and pulmonary alteration in ACE activity of diabetic mice, suggesting a common regulation. The increase of ACE2 activity within the circulation in diabetic mice may be ascribed to a compensatory mechanism of RAS.


id: cord-005386-p37rw8dh
author: Szolnoki, Zoltán
date: 2006
txt: ./txt/cord-005386-p37rw8dh.txt
cache: ./cache/cord-005386-p37rw8dh.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7091324/
doi: 10.1385/nmm:8:3:353
summary:
  title: Coexistence of angiotensin II type-1 receptor A1166C and angiotensin-converting enzyme D/D polymorphism suggests susceptibility for small-vessel-associated ischemic stroke Our results demonstrate that ACE D/D and AT1R 1166C polymorphism were associated with the development of small-vessel ischemic stroke through a mutually facilitatory interplay between them. As both polymorphisms are associated with an enhanced activity of the angiotensin II-AT1R axis, we postulated at a clinical level, a synergistic effect between them as regards the evolution of ischemic stroke. A synergistic effect was found between the AT1R 1166C allele and the homozygous ACE D/D genotype in the small-vessel stroke subgroup (adjusted OR, 3.54; 95% CI, 1.88-7.16; p < 0.0005), the mixed vascular type (adjusted OR, 2.41; 95% CI, 1.2-5.1; p < 0.05), and the overall ischemic stroke group (adjusted OR, 2.42; 95% CI, 1.51-3.82; p < 0.005) ( Table 3 ).

title:
  Coexistence of angiotensin II type-1 receptor A1166C and angiotensin-converting enzyme D/D polymorphism suggests susceptibility for small-vessel-associated ischemic stroke

abstract:
  The renin-angiotensin system plays an important role in the maintenance of blood pressure homeostasis. The angiotensin-converting enzyme (ACE) converts angiotensin I into angiotensin II. Angiotensin II, which binds the angiotensin II type-1 receptor (AT1R), is a potent vasoconstrictor. On a pathophysiological basis, both ACE I/D and AT1R A1166C polymorphism lead to an enhanced activity of the angiotensin II-AT1R axis, thereby possibly contributing to circulatory disturbances. A mutually facilitatory effect may be presumed between the two polymorphisms. We examined whether this synergistic effect is involved in the evolution of different types of ischemic stroke. Genetic and clinical data on 308 consecutive patients with acutely developing ischemic stroke were analyzed. A total of 272 stroke and neuroimaging alteration-free subjects served as a control group. Univariate and logistic regression statistical approaches were used. The ACE D allele combined with the AT1R 1166C allele did not yield a risk of ischemic stroke. However, the co-occurrence of the homozygous ACE D/D and at least one AT1R 1166C allele was more frequent in the ischemic stroke group than in the control group (22.4 vs 11%, p<0.005, OR, 2.33; 95% CI, 1.46–3.7). After specific subgroup analysis, this synergistic association was even stronger for small-vessel ischemic stroke (OR, 3.44; 95% CI, 1.9–6.24; p<0.0005). Multivariate logistic regression analysis of the data confirmed this association (adjusted OR, 3.54, 95% CI, 1.88–7.16; p<0.0005). Our results demonstrate that ACE D/D and AT1R 1166C polymorphism were associated with the development of small-vessel ischemic stroke through a mutually facilitatory interplay between them. Genetic interactions might contribute to the altered functional network in renin-angiotensin system in vascular disorders.


id: cord-005927-a9sj00y8
title: Angiotensin-converting enzyme is a GPI-anchored protein releasing factor crucial for fertilization
author: Kondoh, Gen
date: 2005-01-23
txt: ./txt/cord-005927-a9sj00y8.txt
cache: ./cache/cord-005927-a9sj00y8.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7095966/
doi: 10.1038/nm1179
summary:
  We also assessed the effect of ACE-specific inhibitors, such as captopril and lisinopril, which bind to the catalytic center with ligation of its thiol to the zinc ion and completely inhibit the peptidase activity, but found only a minor inhibitory effect on the GPIase assay ( Fig. 1c , 1 × 10 -3 M captopril produced 40% inhibition and data not shown). We treated cells with ACE, PI-PLC or mouse glandular kallikrein (mGK), which digests EGFP protein near the carboxy termini (data not shown) and trapped the released products from the supernatants using antibody specific for GFP. We collected epididymal sperm from both wild-type and Ace knockout mice 33 and compared the distribution of GPI-anchored proteins in water-soluble and detergent-soluble fractions. In this regard, GPI-anchored proteins were not released in sperms of Ace knockout mice (Fig. 5a) .

abstract:
  The angiotensin-converting enzyme (ACE) is a key regulator of blood pressure. It is known to cleave small peptides, such as angiotensin I and bradykinin and changes their biological activities, leading to upregulation of blood pressure. Here we describe a new activity for ACE: a glycosylphosphatidylinositol (GPI)-anchored protein releasing activity (GPIase activity). Unlike its peptidase activity, GPIase activity is weakly inhibited by the tightly binding ACE inhibitor and not inactivated by substitutions of core amino acid residues for the peptidase activity, suggesting that the active site elements for GPIase differ from those for peptidase activity. ACE shed various GPI-anchored proteins from the cell surface, and the process was accelerated by the lipid raft disruptor filipin. The released products carried portions of the GPI anchor, indicating cleavage within the GPI moiety. Further analysis by high-performance liquid chromatography–mass spectrometry predicted the cleavage site at the mannose-mannose linkage. GPI-anchored proteins such as TESP5 and PH-20 were released from the sperm membrane of wild-type mice but not in Ace knockout sperm in vivo. Moreover, peptidase-inactivated E414D mutant ACE and also PI-PLC rescued the egg-binding deficiency of Ace knockout sperms, implying that ACE plays a crucial role in fertilization through this activity. SUPPLEMENTARY INFORMATION: The online version of this article (doi:10.1038/nm1179) contains supplementary material, which is available to authorized users.


id: cord-005931-iggkxbbf
title: Brain renin angiotensin in disease
author: Phillips, M. Ian
date: 2008-04-02
txt: ./txt/cord-005931-iggkxbbf.txt
cache: ./cache/cord-005931-iggkxbbf.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7095973/
doi: 10.1007/s00109-008-0331-5
summary:
  Transgenic mice and rats bearing renin and extra copies of angiotensinogen genes revealed the importance of brain RAS. Taking the concept a step further, it was reasoned that if ANG II, formed by brain renin, was involved in hypertension, then inhibiting brain RAS would lower blood pressure. Minute injections of ANG II into key brain nuclei showed that ANG II could differentially produce pressor effects, elicit drinking, release vasopressin, inhibit the baroreflex, and increase sympathetic nervous system activity [20, 21] . In the double transgenic mice developed by Sigmund and colleagues [35] , to overexpress both human renin and human AGT so that they constantly have high ANG II levels, antisense to AT1R mRNA dramatically reduced the blood pressure. ACE-2, ANG (1-7), and Mas receptors are all localized in brain areas related to the control of cardiovascular function.

abstract:
  A brain renin angiotensin system (RAS) and its role in cardiovascular control and fluid homeostasis was at first controversial. This was because a circulating kidney-derived renin angiotensin system was so similar and well established. But, the pursuit of brain RAS has proven to be correct. In the course of accepting brain RAS, high standards of proof attracted state of the art techniques in all the new developments of biolo1gy. Consequently, brain RAS is a robust concept that has enlightened neuroscience as well as cardiovascular physiology and is a model neuropeptide system. Molecular biology confirmed the components of brain RAS and their location in the brain. Transgenic mice and rats bearing renin and extra copies of angiotensinogen genes revealed the importance of brain RAS. Cre-lox delivery in vectors has enabled pinpoint gene deletion of brain RAS in discrete brain nuclei. The new concept of brain RAS includes ACE-2, Ang1–7, and prorenin and Mas receptors. Angiotensin II (ANG II) generated in the brain by brain renin has many neural effects. It activates behavioral effects by selective activation of ANG II receptor subtypes in different locations. It regulates sympathetic activity and baroreflexes and contributes to neurogenic hypertension. New findings implicate brain RAS in a much wider range of neural effects. We review brain RAS involvement in Alzheimer’s disease, stroke memory, and learning alcoholism stress depression. There is growing evidence to consider developing treatment strategies for a variety of neurological disease states based on brain RAS.


id: cord-006082-x1kankxd
title: Novel RAAS agonists and antagonists: clinical applications and controversies
author: Romero, Cesar A.
date: 2015-02-10
txt: ./txt/cord-006082-x1kankxd.txt
cache: ./cache/cord-006082-x1kankxd.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7097622/
doi: 10.1038/nrendo.2015.6
summary:
  Despite the important improvements achieved with these agents in slowing the progression of established cardiorenal disease, the ACE inhibitors and the ARBs only provide a 20% reduction in the relative risk of Key points ■ Renin-angiotensin-aldosterone system (RAAS) blockade with an angiotensin converting enzyme inhibitor or an angiotensin receptor blocker provides a 20% relative risk reduction for the progression of established cardiorenal disease compared with other non-RAAS blocking therapies ■ The RAAS is an endocrine, paracrine and autocrine system that regulates blood pressure homeostasis through effects on a variety of target organs, as well as having a role in the responses to vascular injury and repair ■ The RAAS is a complex system with a variety of sites suitable for pharmacological intervention ■ Novel molecules that alter the production of various RAAS peptides or that alter receptor density, function or responsiveness to these peptides could have an important influence on haemodynamics and vascular structure and function www.nature.com/nrendo progression of cardiovascular disease when compared with non-RAAS blocking therapy.

abstract:
  The renin–angiotensin–aldosterone system (RAAS) regulates blood pressure homeostasis and vascular injury and repair responses. The RAAS was originally thought to be an endocrine system critically important in regulating blood pressure homeostasis. Yet, important local forms of the RAAS have been described in many tissues, which are mostly independent of the systemic RAAS. These systems have been associated with diverse physiological functions, but also with inflammation, fibrosis and target-organ damage. Pharmacological modulation of the RAAS has brought about important advances in preventing morbidity and mortality associated with cardiovascular disease. Yet, traditional RAAS blockers such as angiotensin converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) only reduce the risk of disease progression in patients with established cardiovascular or renal disease by ∼20% compared with other therapies. As more components of the RAAS are described, other potential therapeutic targets emerge, which could provide improved cardiovascular and renal protection beyond that provided by an ACE inhibitor or ARB. This Review summarizes the present and future pharmacological manipulation of this important system. SUPPLEMENTARY INFORMATION: The online version of this article (doi:10.1038/nrendo.2015.6) contains supplementary material, which is available to authorized users.


id: cord-006087-hynkb0a8
title: Ace revisited: A new target for structure-based drug design
author: Acharya, K. Ravi
date: 2003
txt: ./txt/cord-006087-hynkb0a8.txt
cache: ./cache/cord-006087-hynkb0a8.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7097707/
doi: 10.1038/nrd1227
summary:
  Current-generation angiotensin-converting enzyme (ACE) inhibitors are widely used for cardiovascular diseases, including high blood pressure, heart failure, heart attack and kidney failure, and have combined annual sales in excess of US $6 billion. Some differences in catalytic properties have been observed for these two sites: the N-domain site is notably 50-times more active toward the haemoregulatory peptide N-acetyl-Ser-Asp-Lys-Pro (AcSDKP) 21 , 1000-times Here, we provide an overview of ACE and the RAS, current ACE inhibitors and their clinical utility, insights from the tACE crystal structure, and the rationale and prospects for developing second-generation, domainselective inhibitors by structure-guided design. BPF was a mixture of peptides 59 , which were shown to be potent and specific inhibitors of ACE (TABLE 1), and structure-activity studies indicated that the optimal C-terminal inhibitory sequence was Phe-Ala-Pro 60 . An important caveat in considering the design and pharmacological utility of domain-selective ACE inhibitors is the potential for conformational effects that have not yet been observed in the tACE crystal structure.

abstract:
  Current-generation angiotensin-converting enzyme (ACE) inhibitors are widely used for cardiovascular diseases, including high blood pressure, heart failure, heart attack and kidney failure, and have combined annual sales in excess of US $6 billion. However, the use of these ACE inhibitors, which were developed in the late 1970s and early 1980s, is hampered by common side effects. Moreover, we now know that ACE actually consists of two parts (called the N- and C-domains) that have different functions. Therefore, the design of specific domain-selective ACE inhibitors is expected to produce next-generation drugs that might be safer and more effective. Here we discuss the structural features of current inhibitors and outline how next-generation ACE inhibitors could be designed by using the three-dimensional molecular structure of human testis ACE. The ACE structure provides a unique opportunity for rational drug design, based on a combination of in silico modelling using existing inhibitors as scaffolds and iterative lead optimization to drive the synthetic chemistry.


id: cord-015859-5kt59ose
title: Local Angiotensin Generation and AT(2) Receptor Activation
author: Esch, Joep H.M. Van
date: 2007
txt: ./txt/cord-015859-5kt59ose.txt
cache: ./cache/cord-015859-5kt59ose.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7119946/
doi: 10.1007/978-1-4020-6372-5_12
abstract: nan
summary:
  Mice lacking the ren-1 d gene are characterized by sexually dimorphic hypotension (leading to a significant reduction of blood pressure in female mice), absence of dense secretory/storage granule formation in juxta-glomerular cells, altered morphology of the kidney, and a significant increase of plasma prorenin levels (Clark et al 1997) . Importantly, binding of (pro)renin to the (pro)renin receptor in human mesangial cells also induced Ang II-independent effects, such as an increase in DNA synthesis, activation of the mitogen-activated protein kinases (MAPKs) extracellular signal-regulated kinase (ERK)1 (p44)/ERK2 (p42), and plasminogenactivator inhibitor-1 release. AT 2 receptors are involved in physiological processes like development and tissue remodeling (by inhibiting cell growth and by stimulating apoptosis), regulation of blood pressure (vasodilatation), natriuresis and neuronal activity. In vitro studies using the isolated perfused rat Langendorff heart fully confirmed the idea of renin and angiotensinogen uptake underlying tissue angiotensin production.


id: cord-016742-y7jgjera
title: Cardiovascular Anatomy and Pharmacology
author: Bauer, Maria
date: 2017-07-03
txt: ./txt/cord-016742-y7jgjera.txt
cache: ./cache/cord-016742-y7jgjera.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7121118/
doi: 10.1007/978-3-319-62067-1_11
summary:
  The binding of an agonist to the adrenergic receptor replaces guanosine diphosphate (GDP) by guanosine triphosphate (GTP), and causes the α-subunit of the G-protein to break free from the β-γ complex, and act as a primary messenger: in beta receptors, it stimulates adenylate cyclase and triggers cyclic adenosine monophosphate (cAMP) production, which, as a second messenger in the process of signal transduction, activates its target kinases that phosphorylate regulator proteins and ultimately increases intracellular calcium levels. Their main anti-ischemic effects are due to their ability to reduce myocardial O 2 consumption by depressing contractility, decreasing heart rate and systemic afterload, and increasing O 2 supply by coronary and collateral vasodilation. Verapamil decreases the heart rate by depressing sinoatrial and AV-nodal activity (hence its utility in the treatment of supraventricular arrhythmias), lowers systemic blood pressure due to myocardial depression and peripheral vasodilation, and produces moderate coronary artery dilation (preferred in essential hypertension and vasospastic angina).

abstract:
  This chapter reviews the cardiovascular anatomy, the effects of medications on the cardiovascular system, and current guidelines. Patients in the perioperative period often receive agents that affect hemodynamic variables such as heart rhythm and rate, blood pressure, or cardiac output.


id: cord-017585-0llgr357
title: Role of ACE, ACE2 and Neprilysin in the Kidney
author: Chappell, Mark C.
date: 2007
txt: ./txt/cord-017585-0llgr357.txt
cache: ./cache/cord-017585-0llgr357.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7122178/
doi: 10.1007/978-1-4020-6372-5_1
abstract: nan
summary:
  Although the emergence of receptor subtypes distinguishes the distinct signaling pathways of Ang II and Ang-(1-7), the post-renin enzymes that form and degrade these peptides must be considered in lieu of the overall regulation of the functional RAAS within the kidney. ACE, angiotensin converting enzyme; EPs, endopeptidases; NEP, neprilysin demonstration of endogenous levels of the peptide in the kidney, circulation and other tissues (Nagata et al 2006) . Thus, in addition to the proximal tubule epithelium, the glomerulus may be a second key site within the kidney where ACE2 may influence the local expression of angiotensin peptides and renal function. There are few studies on the regulation of the Ang-(1-7) receptor, although chronic ACE or AT 1 blockade reduced mas mRNA expression in the renal cortex of the Ren2 Lewis congenic rat .


id: cord-018009-8j40876m
title: ACE Inhibition in Heart Failure and Ischaemic Heart Disease
author: Campbell, Duncan J. John
date: 2007
txt: ./txt/cord-018009-8j40876m.txt
cache: ./cache/cord-018009-8j40876m.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7122740/
doi: 10.1007/978-1-4020-6372-5_2
abstract: nan
summary:
  Angiotensin converting enzyme (dipeptidyl carboxypeptidase I, kininase II, EC 3.4.15.1, ACE) plays a major role in the metabolism of many different peptides, including angiotensin (Ang) I, bradykinin, kallidin, and N-acetyl-seryl-aspartyllysyl-proline (AcSDKP). Pooled analysis of the HOPE, EUROPA, and PEACE trials showed ACE inhibition reduced all cause and cardiovascular mortality, non-fatal myocardial infarction, stroke, heart failure, and coronary artery bypass surgery, leading to the recommendation that ACE inhibitors be considered in all patients with atherosclerosis (Dagenais et al 2006) . ACE inhibitor therapy did not increase either bradykinin or kallidin peptide levels in cardiac atria of patients with ischaemic heart disease, despite the reduction in Ang II levels . Bradykinin contributes to the systemic hemodynamic effects of chronic angiotensin-converting enzyme inhibition in patients with heart failure Interaction between neutral endopeptidase and angiotensin converting enzyme inhibition in rats with myocardial infarction: effects on cardiac hypertrophy and angiotensin and bradykinin peptide levels Bradykinin contributes to the vasodilator effects of chronic angiotensin-converting enzyme inhibition in patients with heart failure


id: cord-024076-q9fw7ch1
author: Manga, Pravin
date: 2020-04-17
txt: ./txt/cord-024076-q9fw7ch1.txt
cache: ./cache/cord-024076-q9fw7ch1.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7187740/
doi: 10.18772/26180197.2020.v2nsia4
abstract: nan
summary:
  The reports urging caution in the use of ACE inhibitors and ARBs for hypertension, diabetes and cardiovascular disease are based on laboratory data which found that SARS-CoV and COVID-19 virus binds to ACE 2 receptor which is found in the epithelial cells of the lung, kidney, intestine and blood vessels. Thus, a clear causal relationship between those with cardiovascular disease, hypertension, heart failure with reduced ejection fraction (HFrEF), and diabetes with chronic kidney disease (DCKD) on ACE inhibitors or ARB treatment and an increased risk of COVID-19 does not exist. In South Africa, hypertension, HFrEF and diabetes are common non-communicable diseases, and a significant proportion of patients are being treated with generic versions of ACE inhibitors or ARBs. There is extremely strong scientific evidence for the benefit of RAAS inhibition in patients with cardiovascular disease.

title:
  Should ACE Inhibitors and Angiotensin Receptor Blockers Be Withdrawn in the Current Setting of COVID-19 Infection?


id: cord-253862-jl1zhg13
title: SARS-CoV-2: Pathogenesis, and Advancements in Diagnostics and Treatment
author: Khalaf, Khalil
date: 2020-10-06
txt: ./txt/cord-253862-jl1zhg13.txt
cache: ./cache/cord-253862-jl1zhg13.txt
extension: .txt
mime: text/plain
url: https://doi.org/10.3389/fimmu.2020.570927
doi: 10.3389/fimmu.2020.570927
summary:
  Although this novel virus is less severe than the first SARS-CoV outbreak, human-to-human transmission remains very high and the number of cases continues to rise exponentially in major urban areas, highlighting the urgent need to develop new containment, diagnostic, and treatment protocols. In the case of SARS-CoV-2, viral evasion of the innate immune system leads to an increase in cytokine production and late CD4+/CD8+ response, which then leads to pathogenic inflammation in patients with high viral loads. (ChiCTR2000029308), involving severe SARS-CoV-2 cases, compared lopinavir/ritonavir treatment with standard care alone, and they showed that the antivirals yielded no clinical benefits. In an open-label control study conducted by Cai et al., the antiviral activity of favipiravir + IFN-α was compared to that of lopinavir/ritonavir + IFN-α in patients with confirmed SARS-CoV-2 infection.

abstract:
  The emergence and rapid spread of SARS-CoV-2 in December 2019 has brought the world to a standstill. While less pathogenic than the 2002–2003 SARS-CoV, this novel betacoronavirus presents a global threat due to its high transmission rate, ability to invade multiple tissues, and ability to trigger immunological hyperactivation. The identification of the animal reservoir and intermediate host were important steps toward slowing the spread of disease, and its genetic similarity to SARS-CoV has helped to determine pathogenesis and direct treatment strategies. The exponential increase in cases has necessitated fast and reliable testing procedures. Although RT-PCR remains the gold standard, it is a time-consuming procedure, paving the way for newer techniques such as serologic tests and enzyme immunoassays. Various clinical trials using broad antiviral agents in addition to novel medications have produced controversial results; however, the advancement of immunotherapy, particularly monoclonal antibodies and immune modulators is showing great promise in clinical trials. Non-orthodox medications such as anti-malarials have been tested in multiple institutions but definitive conclusions are yet to be made. Adjuvant therapies have also proven to be effective in decreasing mortality in the disease course. While no formal guidelines have been established, the multitude of ongoing clinical trials as a result of unprecedented access to research data brings us closer to halting the SARS-CoV-2 pandemic.


id: cord-256020-wrui3i2l
title: Understanding the epidemiology, pathophysiology, diagnosis and management of SARS-CoV-2
author: Fadaka, Adewale Oluwaseun
date: 2020-08-26
txt: ./txt/cord-256020-wrui3i2l.txt
cache: ./cache/cord-256020-wrui3i2l.txt
extension: .txt
mime: text/plain
url: https://doi.org/10.1177/0300060520949077
doi: 10.1177/0300060520949077
summary:
  The disease is caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). The disease is caused by SARS-CoV-2, a zoonotic pathogen that acquired mutations as it crossed the species barrier from bat to pangolin enabling it to infect humans. 5 The clinical symptoms of COVID-19 include fever, cough, and pneumonia, which makes the disease enormously dangerous with a high case fatality rate. 11 Symptoms of human SARS-CoV-1 infections include headache, fever and respiratory complications such as cough, dyspnea, and pneumonia. 81 The main goal of SARS-CoV-2 diagnosis is to accurately detect the virus and to minimize further transmissions by timely isolation and treatment of infected patients. 112 This implies that variation in ACE-2 expression in COVID-19 patients is likely to affect susceptibility, symptoms and intervention outcomes following SARS-CoV-2 infection. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and coronavirus disease-2019 (COVID-19): the epidemic and the challenges Comparative genetic analysis of the novel coronavirus (2019-nCoV/SARS-CoV-2) receptor ACE2 in different populations

abstract:
  The emergence of coronavirus disease 2019 (COVID-19) in December 2019 has resulted in over 20 million cases and 741,808 deaths globally, affecting more than 200 countries. COVID-19 was declared a pandemic on 11 March 2020 by the World Health Organization. The disease is caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). There is limited information on COVID-19, and treatment has so far focused on supportive care and use of repurposed drugs. COVID-19 can be transmitted via person-to-person contact through droplet spread. Some of the recommended precautionary measures to reduce the rate of disease spread include social distancing, good hygiene practices, and avoidance of crowded areas. These measures are effective because the droplets are heavy and can only travel approximately 1 meter in the air, settling quickly on fixed surfaces. Promising strategies to combat SARS-CoV-2 include discovery of therapeutic targets/drugs and vaccines. In this review, we summarize the epidemiology, pathophysiology, and diagnosis of COVID-19. We also address the mechanisms of action of approved repurposed drugs for therapeutic management of the disease.


id: cord-259933-ggx4v0bz
title: The ACE-2 in COVID-19: Foe or Friend?
author: Dalan, Rinkoo
date: 2020-04-27
txt: ./txt/cord-259933-ggx4v0bz.txt
cache: ./cache/cord-259933-ggx4v0bz.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pubmed/32340044/
doi: 10.1055/a-1155-0501
summary:
  The SARS-CoV-2, a positive strand RNA virus, has been seen to infect humans through the angiotensin converting enzyme -2 (ACE-2) receptor [9] . In individuals with hypertension, diabetes, and other cardiovascular disorders with vascular complications, the renin angiotensin system (RAS) is known to be activated with an increase in ACE activity and a downregulation of ACE-2. Therefore, it may be assumed that the inherent downregulation of the ACE-2-Ang-(1-7)-Mas axis (as seen in metabolic conditions) is exacerbated in the COVID-19 state because (i) the virus uses the peptidase domain of the enzyme for entry into the cells and (ii) there is a decrease in ACE-2 with an increase in ACE [9] . Individuals with underlying hypertension, type 2 diabetes, or cardiovascular disease are at higher risk for respiratory failure and mortality in COVID-19.

abstract:
  COVID-19 is a rapidly spreading outbreak globally. Emerging evidence demonstrates that older individuals and people with underlying metabolic conditions of diabetes mellitus, hypertension, and hyperlipidemia are at higher risk of morbidity and mortality. The SARS-CoV-2 infects humans through the angiotensin converting enzyme (ACE-2) receptor. The ACE-2 receptor is a part of the dual system renin-angiotensin-system (RAS) consisting of ACE-Ang-II-AT (1) R axis and ACE-2-Ang-(1–7)-Mas axis. In metabolic disorders and with increased age, it is known that there is an upregulation of ACE-Ang-II-AT (1) R axis with a downregulation of ACE-2-Ang-(1–7)-Mas axis. The activated ACE-Ang-II-AT1R axis leads to pro-inflammatory and pro-fibrotic effects in respiratory system, vascular dysfunction, myocardial fibrosis, nephropathy, and insulin secretory defects with increased insulin resistance. On the other hand, the ACE-2-Ang-(1–7)-Mas axis has anti-inflammatory and antifibrotic effects on the respiratory system and anti-inflammatory, antioxidative stress, and protective effects on vascular function, protects against myocardial fibrosis, nephropathy, pancreatitis, and insulin resistance. In effect, the balance between these two axes may determine the prognosis. The already strained ACE-2-Ang-(1–7)-Mas in metabolic disorders is further stressed due to the use of the ACE-2 by the virus for entry, which affects the prognosis in terms of respiratory compromise. Further evidence needs to be gathered on whether modulation of the renin angiotensin system would be advantageous due to upregulation of Mas activation or harmful due to the concomitant ACE-2 receptor upregulation in the acute management of COVID-19.


id: cord-264828-6w13xo2a
author: Albini, Adriana
date: 2020-05-19
txt: ./txt/cord-264828-6w13xo2a.txt
cache: ./cache/cord-264828-6w13xo2a.txt
extension: .txt
mime: text/plain
url: https://doi.org/10.1007/s11739-020-02364-6
doi: 10.1007/s11739-020-02364-6
summary:
  Older COVID-19-affected patients with cardiovascular comorbidities exhibit a more severe clinical course and a worse prognosis, with many of them being also treated with ARBs or ACE-Is. Another confounding factor is cigarette smoking, which has been reported to increase ACE-2 expression in both experimental models and humans. 4. Renin-angiotensin-aldosterone system (RAAS)-interfering drugs are likely to affect ACE-2 receptor-SARS-CoV-2 interaction dynamics within lung, heart, vascular, kidney and gut tissues [5, 19] , while it is still not completely elucidated how such interactions are relevant to the clinical course of cardiovascular comorbidities in patients with COVID-19 [29] . Consequently, the up-regulation of human ACE-2 induced by RAAS-antagonists in SARS-CoV-2-infected patients could be clinically useful, due to the cardiovascular protection elicited by the increased activity of angiotensin(1-7), thereby attenuating angiotensin II effects on vasoconstriction and sodium retention [31, 34] .

title:
  The SARS-CoV-2 receptor, ACE-2, is expressed on many different cell types: implications for ACE-inhibitor- and angiotensin II receptor blocker-based cardiovascular therapies

abstract:
  SARS-CoV-2 is characterized by a spike protein allowing viral binding to the angiotensin-converting enzyme (ACE)-2, which acts as a viral receptor and is expressed on the surface of several pulmonary and extra-pulmonary cell types, including cardiac, renal, intestinal and endothelial cells. There is evidence that also endothelial cells are infected by SARS-COV-2, with subsequent occurrence of systemic vasculitis, thromboembolism and disseminated intravascular coagulation. Those effects, together with the “cytokine storm” are involved in a worse prognosis. In clinical practice, angiotensin-converting enzyme inhibitors (ACE-Is) and angiotensin II receptor blockers (ARBs) are extensively used for the treatment of hypertension and other cardiovascular diseases. In in vivo studies, ACE-Is and ARBs seem to paradoxically increase ACE-2 expression, which could favour SARS-CoV-2 infection of host’s cells and tissues. By contrast, in patients treated with ACE-Is and ARBs, ACE-2 shows a downregulation at the mRNA and protein levels in kidney and cardiac tissues. Yet, it has been claimed that both ARBs and ACE-Is could result potentially useful in the clinical course of SARS-CoV-2-infected patients. As detected in China and as the Italian epidemiological situation confirms, the most prevalent comorbidities in deceased patients with COVID-19 are hypertension, diabetes and cardiovascular diseases. Older COVID-19-affected patients with cardiovascular comorbidities exhibit a more severe clinical course and a worse prognosis, with many of them being also treated with ARBs or ACE-Is. Another confounding factor is cigarette smoking, which has been reported to increase ACE-2 expression in both experimental models and humans. Sex also plays a role, with chromosome X harbouring the gene coding for ACE-2, which is one of the possible explanations of why mortality in female patients is lower. Viral entry also depends on TMPRSS2 protease activity, an androgen dependent enzyme. Despite the relevance of experimental animal studies, to comprehensively address the question of the potential hazards or benefits of ACE-Is and ARBs on the clinical course of COVID-19-affected patients treated by these anti-hypertensive drugs, we will need randomized human studies. We claim the need of adequately powered, prospective studies aimed at answering the following questions of paramount importance for cardiovascular, internal and emergency medicine: Do ACE-Is and ARBs exert similar or different effects on infection or disease course? Are such effects dangerous, neutral or even useful in older, COVID-19-affected patients? Do they act on multiple cell types? Since ACE-Is and ARBs have different molecular targets, the clinical course of SARS-CoV-2 infection could be also different in patients treated by one or the other of these two drug classes. At present, insufficient detailed data from trials have been made available.


id: cord-266289-dkxhbmic
title: ACE for all – a molecular perspective
author: Harrison, Charlotte
date: 2014-07-16
txt: ./txt/cord-266289-dkxhbmic.txt
cache: ./cache/cord-266289-dkxhbmic.txt
extension: .txt
mime: text/plain
url: http://europepmc.org/articles/pmc4165820?pdf=render
doi: 10.1007/s12079-014-0236-8
summary:
  The involvement of ACE in processes outside of blood pressure regulation, and in particular the differences in substrate specificity of the two domains of sACE highlight the growing need for a new generation of ACE inhibitors. Interestingly, the two residues that differ; Arg381/Glu403 and Tyr369/Phe391 are located in the S 2 subsite (Fig. 5d ), further illustrating that interactions between the enzyme and inhibitors at this site are an important determinant of domain selectivity. The N domain of human angiotensin-I-converting enzyme: the role of Nglycosylation and the crystal structure in complex with an N domain-specific phosphinic inhibitor, RXP407 The structure of testis angiotensin-converting enzyme in complex with the C domain-specific inhibitor RXPA380

abstract:
  Angiotensin-I converting enzyme (ACE, EC 3.4.15.1) is a zinc dependent dipeptidyl carboxypeptidase with an essential role in mammalian blood pressure regulation as part of the renin-angiotensin aldosterone system (RAAS). As such, it has long been targeted in the treatment of hypertension through the use of ACE inhibitors. Although ACE has been studied since the 1950s, only recently have the full range of functions of this enzyme begun to truly be appreciated. ACE homologues have been found in a host of other organisms, and are now known to be conserved in insects. Insect ACE homologues typically share over 30 % amino acid sequence identity with human ACE. Given that insects lack a mammalian type circulatory system, they must have crucial roles in other physiological processes. The first ACE crystal structures were reported during the last decade and have enabled these enzymes to be studied from an entirely different perspective. Here we review many of these key developments and the implications that they have had on our understanding of the diverse functions of these enzymes. Specifically, we consider how structural information is being used in the design of a new generation of ACE inhibitors with increased specificity, and how the structures of ACE homologues are related to their functions. The Anopheles gambiae genome is predicted to code for ten ACE homologues, more than any genome studied so far. We have modelled the active sites of some of these as yet uncharacterised enzymes to try and infer more about their potential roles at the molecular level.


id: cord-266755-y2lf7ssp
title: ACEIs and ARBs and Their Correlation with COVID-19: A Review
author: Yehualashet, Awgichew Shewasinad
date: 2020-09-16
txt: ./txt/cord-266755-y2lf7ssp.txt
cache: ./cache/cord-266755-y2lf7ssp.txt
extension: .txt
mime: text/plain
url: https://doi.org/10.2147/idr.s264882
doi: 10.2147/idr.s264882
summary:
  21, 22 Both ACE-1 and ACE-2 cleave angiotensin peptides in that ACE-1 cleaves angiotensin I and generating angiotensin (Ang) II, which causes vasoconstriction, bronchoconstriction, increases vascular permeability, inflammation, and fibrosis and enhance the development of acute respiratory disease syndrome (ARDS) and lung failure in patients infected with SARS-CoV-2. 36 The probable rational proposed for the possible relation between the use of ACEIs/ARBs, and progression to ARDS in COVID-19 is the increased availability of ACE-2 attached to surface in the lung endothelium, an inherent effect of these two classes, leading to enhanced coupling of SARS-CoV2 to ACE-2 and its consequent cell entry. Based on prior animal studies, it was suggested that proposed ACEIs and ARBs can enhance ACE2 activity and thereby increase infectivity of COVID-19 virus. 48 In severe lung injury animal models, preclinical studies have showed that ACE2 is significantly downregulated and it has been shown that the inhibition of the angiotensin type 1 receptor by ARB like losartan reduces severe acute lung injury in mice administered with the spike glycoprotein of SARS-CoV.

abstract:
  Although some animal studies suggested that the use of ACEIs/ARBs could contribute for the prevention and treatment of the effects of the COVID-19 infection, there are also contradictory scenarios indicating that their use may exacerbate the deleterious conditions of the infection. As a result of the paradoxical issue of using ACEIs/ARBs during COVID-19, it is still an area requiring extended investigation to prove. Additionally, a trial evidence of their efficacy and the possible benefit risk analysis of these conventional drugs during COVID-19 in connection with other comorbidities like hypertension, heart failure, and renal disease associated with diabetes should also be addressed.


id: cord-267519-a0bcmjkn
author: Bravi, Francesca
date: 2020-06-24
txt: ./txt/cord-267519-a0bcmjkn.txt
cache: ./cache/cord-267519-a0bcmjkn.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pubmed/32579597/
doi: 10.1371/journal.pone.0235248
summary:
  AIMS: This retrospective case-control study was aimed at identifying potential independent predictors of severe/lethal COVID-19, including the treatment with Angiotensin-Converting Enzyme inhibitors (ACEi) and/or Angiotensin II Receptor Blockers (ARBs). Observing that human pathogenic coronaviruses bind their target cells through angiotensin-converting enzyme 2 (ACE2) [5] [6] [7] [8] , and that a few studies reported an increase in ACE2 expression mediated by angiotensin II type-I receptor blockers (ARBs) and ACE inhibitors (more consistently on animals than in humans) [9] [10] [11] [12] [13] [14] [15] [16] , some hypothesized that the increased expression of ACE2 would facilitate infection with Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), thus the hypertension treatment with ACE2-stimulating drugs, as well as ACE2 polymorphisms, might increase the risk of developing severe COVID-19 [17] [18] [19] .

title:
  Predictors of severe or lethal COVID-19, including Angiotensin Converting Enzyme inhibitors and Angiotensin II Receptor Blockers, in a sample of infected Italian citizens

abstract:
  AIMS: This retrospective case-control study was aimed at identifying potential independent predictors of severe/lethal COVID-19, including the treatment with Angiotensin-Converting Enzyme inhibitors (ACEi) and/or Angiotensin II Receptor Blockers (ARBs). METHODS AND RESULTS: All adults with SARS-CoV-2 infection in two Italian provinces were followed for a median of 24 days. ARBs and/or ACEi treatments, and hypertension, diabetes, cancer, COPD, renal and major cardiovascular diseases (CVD) were extracted from clinical charts and electronic health records, up to two years before infection. The sample consisted of 1603 subjects (mean age 58.0y; 47.3% males): 454 (28.3%) had severe symptoms, 192 (12.0%) very severe or lethal disease (154 deaths; mean age 79.3 years; 70.8% hypertensive, 42.2% with CVD). The youngest deceased person aged 44 years. Among hypertensive subjects (n = 543), the proportion of those treated with ARBs or ACEi were 88.4%, 78.7% and 80.6% among patients with mild, severe and very severe/lethal disease, respectively. At multivariate analysis, no association was observed between therapy and disease severity (Adjusted OR for very severe/lethal COVID-19: 0.87; 95% CI: 0.50–1.49). Significant predictors of severe disease were older age (with AORs largely increasing after 70 years of age), male gender (AOR: 1.76; 1.40–2.23), diabetes (AOR: 1.52; 1.05–2.18), CVD (AOR: 1.88; 1.32–2.70) and COPD (AOR: 1.88; 1.11–3.20). Only gender, age and diabetes also predicted very severe/lethal disease. CONCLUSION: No association was found between COVID-19 severity and treatment with ARBs and/or ACEi, supporting the recommendation to continue medication for all patients unless otherwise advised by their physicians.


id: cord-269151-r426u5dz
title: Should Angiotensin-Converting Enzyme Inhibitors ever Be Used for the Management of Hypertension?
author: Turner, Jeffrey M.
date: 2020-07-09
txt: ./txt/cord-269151-r426u5dz.txt
cache: ./cache/cord-269151-r426u5dz.txt
extension: .txt
mime: text/plain
url: https://doi.org/10.1007/s11886-020-01352-8
doi: 10.1007/s11886-020-01352-8
summary:
  More recently, a number of indirect comparisons with pooled analysis of several randomized placebo control trials have been done to further elucidate whether ACE inhibitors and ARBs have differing effects on the risk of myocardial infarction [16] [17] [18] [19] . Finally, in the previously mentioned Bangalore paper, a separate meta-analysis of the only head to head trials between ACE inhibitors and ARBs also showed no difference in the risk for myocardial infarction or cardiovascular death between the two classes [16] . Angiotensin-converting enzyme inhibitors and angiotensin receptor blockers have resulted in significant improvements in outcomes related to congestive heart failure, cardiovascular disease, diabetes, stroke, and kidney disease. A meta-analysis reporting effects of angiotensinconverting enzyme inhibitors and angiotensin receptor blockers in patients without heart failure Effect of angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers on all-cause mortality, cardiovascular deaths, and cardiovascular events in patients with diabetes mellitus: a meta-analysis

abstract:
  PURPOSE OF REVIEW: Angiotensin-converting enzyme inhibitors and angiotensin receptor blockers are commonly used anti-hypertensive medications in a number of clinical settings. They are often used interchangeably, but we pose the provocative question as to whether they should be. We review the literature to evaluate for any differences in efficacy between the two classes in order to determine if the greater side effects associated with angiotensin-converting enzyme inhibitors are offset by any advantageous effects on outcomes to warrant their use over angiotensin receptor blockers. RECENT FINDINGS: In many clinical scenarios, the data supports similar efficacy between ACE inhibitors and ARBs, while in a minority of others, there are murky signals from previous trials that suggest ACE inhibitors may be better. However, when reviewing the literature in its entirety, and taking into account recently published pooled analysis and head to head trials, it is reasonable to conclude that ACE inhibitors and ARBs have similar efficacy. This is in contrast to data on adverse effects, which consistently favors the use of ARBs. SUMMARY: From the available data, it is reasonable to conclude that ACE inhibitors and ARBs have equal efficacy yet unequal adverse effects. It is in this context that we take the provocative stance that ACE inhibitors should not be used to treat hypertension.


id: cord-269776-hj1s3ipp
author: Agostoni, Angelo
date: 2004-09-11
txt: ./txt/cord-269776-hj1s3ipp.txt
cache: ./cache/cord-269776-hj1s3ipp.txt
extension: .txt
mime: text/plain
url: https://www.sciencedirect.com/science/article/pii/S0091674904017579
doi: 10.1016/j.jaci.2004.06.047
summary:
  Concerning HAE-I and HAE-II, just as variations in serum concentrations of APP appear to determine which individuals in a normal population develop angioedema with a second perturbation of kinin metabolism, such as the use of ACE inhibitors, 96 it could be speculated that variations in either kinin activation or inactivation pathways might contribute to the differences in severity of angioedema in individuals with a pre-existing perturbation in kinin metabolism, such as a mutation in C1-INH (as occurs in HAE). 13, 14, 27 This increase in plasma bradykinin was demonstrated both for patients with HAE with C1-INH deficiency and for patients with drug-associated angioedema who had an angioedematous attack in conjunction with ACE inhibitor treatment. The patient''s daughter had recurrent skin angioedema and gastrointestinal pain attacks since age 12 years; therefore, with a normal C1-INH concentration and activity in both mother and daughter, a diagnosis of HAE type III was assumed.

title:
  Hereditary and acquired angioedema: Problems and progress: Proceedings of the third C1 esterase inhibitor deficiency workshop and beyond

abstract:
  Hereditary angioedema (HAE), a rare but life-threatening condition, manifests as acute attacks of facial, laryngeal, genital, or peripheral swelling or abdominal pain secondary to intra-abdominal edema. Resulting from mutations affecting C1 esterase inhibitor (C1-INH), inhibitor of the first complement system component, attacks are not histamine-mediated and do not respond to antihistamines or corticosteroids. Low awareness and resemblance to other disorders often delay diagnosis; despite availability of C1-INH replacement in some countries, no approved, safe acute attack therapy exists in the United States. The biennial C1 Esterase Inhibitor Deficiency Workshops resulted from a European initiative for better knowledge and treatment of HAE and related diseases. This supplement contains work presented at the third workshop and expanded content toward a definitive picture of angioedema in the absence of allergy. Most notably, it includes cumulative genetic investigations; multinational laboratory diagnosis recommendations; current pathogenesis hypotheses; suggested prophylaxis and acute attack treatment, including home treatment; future treatment options; and analysis of patient subpopulations, including pediatric patients and patients whose angioedema worsened during pregnancy or hormone administration. Causes and management of acquired angioedema and a new type of angioedema with normal C1-INH are also discussed. Collaborative patient and physician efforts, crucial in rare diseases, are emphasized. This supplement seeks to raise awareness and aid diagnosis of HAE, optimize treatment for all patients, and provide a platform for further research in this rare, partially understood disorder.


id: cord-275837-2avxd80i
title: COVID -19 outbreak – Diabetes aspect and perspective
author: Ahirwar, Ashok Kumar
date: 2020-05-19
txt: ./txt/cord-275837-2avxd80i.txt
cache: ./cache/cord-275837-2avxd80i.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pubmed/32551334/
doi: 10.1016/j.cmrp.2020.05.005
abstract: nan
summary:
  Diabetes increases the risk of pneumonia in COVID-19 infected individual and it is an important risk factor for adverse outcome. ACE inhibitor and Angiotensin II Receptor Blockers (ARBs) are the few of drugs used for the appropriate management of diabetic patients. All these may lead to increased severity of COVID-19 infection in diabetic individuals. [4] Moreover, genetic polymorphism of ACE receptor has been shown to be linked with diabetes and it might also facilitate COVID-19 infections. [4] On contrary to this, some researchers say that use of ACE inhibitor or ARBs prevents the binding of COVID-19 virus to ACE receptor and thus may prevent infection. [5] All these are the lacunae in the existing knowledge of ACE inhibitor or ARBs use in diabetic individuals. Are patients with hypertension and diabetes mellitus at increased risk for COVID-19 infection?


id: cord-277766-rxmpi61o
author: Guang, Cuie
date: 2012-06-15
txt: ./txt/cord-277766-rxmpi61o.txt
cache: ./cache/cord-277766-rxmpi61o.txt
extension: .txt
mime: text/plain
url: https://www.sciencedirect.com/science/article/pii/S1875213612000952
doi: 10.1016/j.acvd.2012.02.010
summary:
  In a classical RAS, the substrate angiotensinogen (AGT), which is released into the circulation from the liver, is degraded by the enzyme renin that originates in the kidney, generating the inactive angiotensin I (Ang I). The initial drug development of clinical ACE inhibitors was based on the assumption of an active site related to that of carboxypeptidase A but organized to remove a dipeptide rather than a single amino acid from the Cterminus of its substrate. The protective role of XNT against hypertension-induced cardiac fibrosis is associated with activation of ACE2, increases in Ang-(1-7) and inhibition of extracellular signal-regulated kinases [83] . The hemoregulatory peptide N-acetyl-Ser-Asp-Lys-Pro is a natural and specific substrate of the N-terminal active site of human angiotensinconverting enzyme The N-terminal active centre of human angiotensin-converting enzyme degrades Alzheimer amyloid beta-peptide Angiotensin-converting enzyme 2 activation protects against hypertension-induced cardiac fibrosis involving extracellular signal-regulated kinases

title:
  Three key proteases – angiotensin-I-converting enzyme (ACE), ACE2 and renin – within and beyond the renin-angiotensin system

abstract:
  The discovery of angiotensin-I-converting enzyme 2 (ACE2) and a (pro)renin receptor has renewed interest in the physiology of the renin-angiotensin system (RAS). Through the ACE2/angiotensin-(1–7)/Mas counter-regulatory axis, ACE2 balances the vasoconstrictive, proliferative, fibrotic and proinflammatory effects of the ACE/angiotensin II/AT1 axis. The (pro)renin receptor system shows an angiotensin-dependent function related to increased generation of angiotensin I, and an angiotensin-independent aspect related to intracellular signalling. Activation of ACE2 and inhibition of ACE and renin have been at the core of the RAS regulation. The aim of this review is to discuss the biochemistry and biological functions of ACE, ACE2 and renin within and beyond the RAS, and thus provide a perspective for future bioactives from natural plant and/or food resources related to the three proteases.


id: cord-282256-lqmixm7s
author: Tsioufis, Costas
date: 2020-05-22
txt: ./txt/cord-282256-lqmixm7s.txt
cache: ./cache/cord-282256-lqmixm7s.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pubmed/32450334/
doi: 10.1016/j.hjc.2020.05.003
abstract: nan
summary:
  4 The only available meta-analysis from Wuhan of 46248 cases, supports that hypertension constitutes the most prevalent comorbidity in 17% of patients infected with the novel coronavirus. In Italy the most current analysis shows that of 69.1% of the deceased patients were hypertensives and 30% used angiotensin converting enzyme inhibitors (ACEIs) and 17% angiotensin receptor blockers (ARBs). 18 After adjustment for confounders there was no independent association for the use of ACEIs/ARBs with susceptibility for infection or worse clinical outcome in contrast to loop diuretics that were linked to enhanced risk. Hypertension, the renin-angiotensin system, and the risk of lower respiratory tract infections and lung injury: implications for COVID-19 Risk of pneumonia associated with use of angiotensin converting enzyme inhibitors and angiotensin receptor blockers: systematic review and meta-analysis Association of Inpatient Use of Angiotensin Converting Enzyme Inhibitors and Angiotensin II Receptor Blockers with Mortality Among Patients With Hypertension Hospitalized With COVID-19

title:
  The interplay of Hypertension, ACE-2 and SARS-CoV-2: Emerging data as the “Ariadne’s thread” for the “labyrinth” of COVID-19


id: cord-286638-bqxyb61p
title: Diabetes in COVID-19: Prevalence, pathophysiology, prognosis and practical considerations
author: Singh, Awadhesh Kumar
date: 2020-04-09
txt: ./txt/cord-286638-bqxyb61p.txt
cache: ./cache/cord-286638-bqxyb61p.txt
extension: .txt
mime: text/plain
url: https://doi.org/10.1016/j.dsx.2020.04.004
doi: 10.1016/j.dsx.2020.04.004
summary:
  The disease burden of coronavirus infectious disease 2019 (COVID-19) caused by Severe Acute Respiratory Syndrome Coronavirus-2 (SARS CoV-2) has been increasing continuously with more than a million confirmed patients and more than 45 thousand deaths globally [1] . Emerging data suggests that COVID-19 is common in patients with diabetes, hypertension, and cardiovascular disease (CVD), although the prevalence rate varied in different studies as well in country-wise data. Evolving data also suggest that patients of COVID-19 with diabetes are more often associated with severe or critical disease varying from 14 to 32% in different studies [15e18, 20, 22, 24] . Though there is limited data about the association of blood glucose levels with disease course in COVID-19 at present, data from other infections like SARS and influenza H1N1 has shown that patients with poor glycemic control have increased risk of complications and death [60, 61] .

abstract:
  BACKGROUND AND AIMS: High prevalence of diabetes makes it an important comorbidity in patients with COVID-19. We sought to review and analyze the data regarding the association between diabetes and COVID-19, pathophysiology of the disease in diabetes and management of patients with diabetes who develop COVID-19 infection. METHODS: PubMed database and Google Scholar were searched using the key terms ‘COVID-19’, ‘SARS-CoV-2’, ‘diabetes’, ‘antidiabetic therapy’ up to April 2, 2020. Full texts of the retrieved articles were accessed. RESULTS: There is evidence of increased incidence and severity of COVID-19 in patients with diabetes. COVID-19 could have effect on the pathophysiology of diabetes. Blood glucose control is important not only for patients who are infected with COVID-19, but also for those without the disease. Innovations like telemedicine are useful to treat patients with diabetes in today’s times.


id: cord-286825-bu7j7kdr
author: Macours, Nathalie
date: 2004-10-04
txt: ./txt/cord-286825-bu7j7kdr.txt
cache: ./cache/cord-286825-bu7j7kdr.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pubmed/15464852/
doi: 10.1016/s0074-7696(04)39002-9
summary:
  Because this peptide has been found to be an in vivo substrate specific for the N domain of sACE, it is suggested that ACE is implicated in the process of hematopoietic stem cell regulation by permanently degrading this natural circulating inhibitor (Azizi et al., 2001; Rousseau et al., 1995) . At present mammalian M13 family of zinc proteases consists of seven known members: neutral endopeptidase (NEP); the endothelin-converting enzymes ECE-1, ECE-2, and ECE-3; the Kell blood group antigen (Kell); the phosphate regulating gene (PEX); X-converting enzyme (XCE); and secreted endopeptidase (SEP). Sequencing, expression and biochemical characterization of the Porphyromonas gingivalis pepO gene encoding a protein homologous to human endothelin-converting enzyme Functional conservation of the active sites of human and Drosophila angiotensin I-converting enzyme Peptidyl dipeptidases (Ance and Acer) of Drosophila melanogaster: Major diVerences in the substrate specificity of two homologs of human angiotensin I-converting enzyme

title:
  Structure, Evolutionary Conservation, and Functions of Angiotensin- and Endothelin-Converting Enzymes

abstract:
  Angiotensin-converting enzyme, a member of the M2 metalloprotease family, and endothelin-converting enzyme, a member of the M13 family, are key components in the regulation of blood pressure and electrolyte balance in mammals. From this point of view, they serve as important drug targets. Recently, the involvement of these enzymes in the development of Alzheimer's disease was discovered. The existence of homologs of these enzymes in invertebrates indicates that these enzyme systems are highly conserved during evolution. Most invertebrates lack a closed circulatory system, which excludes the need for blood pressure regulators. Therefore, these organisms represent excellent targets for gaining new insights and revealing additional physiological roles of these important enzymes. This chapter reviews the structural and functional aspects of ACE and ECE and will particularly focus on these enzyme homologues in invertebrates.


id: cord-289144-d6fgs8qg
author: Sieńko, Jerzy
date: 2020-07-21
txt: ./txt/cord-289144-d6fgs8qg.txt
cache: ./cache/cord-289144-d6fgs8qg.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pubmed/32764907/
doi: 10.2147/cia.s261516
summary:
  Moreover, there is evidence that ACE genotype affects the outcomes of acute respiratory distress syndrome (ARDS) treatment, the most severe consequence of SARS-CoV-2 infection. 8, 13 The aim of this narrative review was to analyze and identify the mechanisms of ACE-I and ARBs with particular emphasis on angiotensin receptors and their polymorphism in the light of COVID-19 pandemic as these medications are commonly prescribed to elderly patients. 8, 13 The aim of this narrative review was to analyze and identify the mechanisms of ACE-I and ARBs with particular emphasis on angiotensin receptors and their polymorphism in the light of COVID-19 pandemic as these medications are commonly prescribed to elderly patients. 63 This upregulation of the ACE2 receptor causes an increase in SARS-CoV-2 binding sites, which can lead to COVID-19 infection. Association of inpatient use of angiotensin converting enzyme inhibitors and angiotensin II receptor blockers with mortality among patients with hypertension hospitalized with COVID-19

title:
  COVID-19: The Influence of ACE Genotype and ACE-I and ARBs on the Course of SARS-CoV-2 Infection in Elderly Patients

abstract:
  Since the beginning of 2020, the whole world has been struggling with the pandemic of Coronavirus Disease 2019 (COVID-19) caused by a novel coronavirus SARS-CoV-2. The SARS-CoV-2 infection depends on ACE2, TMPRSS2, and CD147, which are expressed on host cells. Several studies suggest that some single nucleotide polymorphisms (SNPs) of ACE2 might be a risk factor of COVID-19 infection. Genotypes affect ACE2 structure, its serum concentration, and levels of circulating angiotensin (1-7). Moreover, there is evidence that ACE genotype affects the outcomes of acute respiratory distress syndrome (ARDS) treatment, the most severe consequence of SARS-CoV-2 infection. COVID-19 morbidity, infection course, and mortality might depend on ACE D allele frequency. The aim of this narrative review was to analyze and identify the mechanisms of ACE-I and ARBs with particular emphasis on angiotensin receptors and their polymorphism in the light of COVID-19 pandemic as these medications are commonly prescribed to elderly patients. There is no direct evidence yet for ACE-I or ARBs in the treatment of COVID-19. However, for those already taking these medications, both the European Society of Cardiology and the American College of Cardiology recommend continuing the treatment, because at present, there is no clear clinical or scientific evidence to justify the discontinuation of ACE-I or ARBs. Individualized treatment decisions should be based on the clinical condition and co-morbidities of each patient.


id: cord-289477-cjm7qhr4
title: Potentiation of bradykinin actions by analogues of the bradykinin potentiating nonapeptide BPP(9α)
author: Mueller, Sylvia
date: 2005-04-25
txt: ./txt/cord-289477-cjm7qhr4.txt
cache: ./cache/cord-289477-cjm7qhr4.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pubmed/15949642/
doi: 10.1016/j.peptides.2005.03.046
summary:
  Synthetic analogues of the bradykinin potentiating nonapeptide BPP(9α) indicate significantly different structural requirements for potentiation of the bradykinin (BK)-induced smooth muscle contraction (GPI) and the inhibition of isolated somatic angiotensin I-converting enzyme (ACE). As initial experimentation on the potentiation of the bradykinin action was primarily performed on isolated smooth muscle organs, in the last decade the potentiating activity was mainly investigated on the affinity and density of the receptor [54] , the intracellular mobilization of Ca 2+ [49, 54] , the release of arachidonic acid [49, 54] , of inositol phosphates [54] , and of nitric oxide [37] . Table 1 Analogues of the bradykinin potentiating peptide BPP 9␣ (TEPROTIDE) with distinct differences between potentiation of the BK-induced contraction of the isolated guinea pig ileum (GPI) and inhibition of the isolated angiotensin I-converting enzyme (ACE)

abstract:
  Synthetic analogues of the bradykinin potentiating nonapeptide BPP(9α) indicate significantly different structural requirements for potentiation of the bradykinin (BK)-induced smooth muscle contraction (GPI) and the inhibition of isolated somatic angiotensin I-converting enzyme (ACE). The results disprove the ACE inhibition as the only single mechanism and also the direct interaction of potentiating peptides with the bradykinin receptors in transfected COS-7 cells as molecular mechanism of potentiation. Our results indicate a stimulation of inositol phosphates (IP(n)) formation independently from the B(2) receptor. Furthermore, the results with La(3+) support the role of extracellular Ca(2+) and its influx through corresponding channels. The missing effect of calyculin on the GPI disproves the role of phosphatases in the potentiating action. These experimental studies should not only contribute to a better understanding of the potentiating mechanisms but also incorporate a shift in the research towards the immune system, in particular towards the immunocompetent polymorphonuclear leukocytes. The chemotaxis of these cells can be potentiated most likely by exclusive inhibition of the enzymatic degradation of bradykinin. Thus the obtained results give evidence that the potentiation of the bradykinin action can occur by different mechanisms, depending on the system and on the applied potentiating factor.


id: cord-290148-6cxndab8
title: Potential harmful effects of discontinuing ACE-inhibitors and ARBs in COVID-19 patients
author: Rossi, Gian Paolo
date: 2020-04-06
txt: ./txt/cord-290148-6cxndab8.txt
cache: ./cache/cord-290148-6cxndab8.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pubmed/32250244/
doi: 10.7554/elife.57278
summary:
  The discovery of angiotensin converting enzyme-2 (ACE-2) as the receptor for SARSCoV-2 (Severe Acute Respiratory Syndrome Coronavirus-2) has implicated the renin-angiotensin-aldosterone system in acute respiratory distress syndrome (ARDS) and respiratory failure in patients with coronavirus disease-19 (COVID-19). However, they differ markedly: ACE-1 cleaves the dipeptide His-Leu from angiotensin I, thus generating angiotensin (Ang) II, which causes vaso-and broncho-constriction, increases vascular permeability, inflammation, and fibrosis and thereby promotes the development of ARDS and lung failure in patients infected with the SARS-CoV and SARS-CoV-2 (Yang et al., 2015) (Figure 1, panel B) . In one commentary ACE-2 was suggested to be secreted at higher amounts in patients with cardiovascular disease than in healthy individuals, and in another, it was also stated that ''ACE-2 levels can be increased by the use of ACEIs'' , albeit no evidence of this occurring in the lungs Mechanisms of COVID-19 by which the SARS-COV-2 virus infects the lower airway cells and modalities to increase circulating soluble ACE-2 for therapeutic use.

abstract:
  The discovery of angiotensin converting enzyme-2 (ACE-2) as the receptor for SARS- CoV-2 (Severe Acute Respiratory Syndrome Coronavirus-2) has implicated the renin-angiotensin-aldosterone system in acute respiratory distress syndrome (ARDS) and respiratory failure in patients with coronavirus disease-19 (COVID-19). The angiotensin converting enzyme-1–angiotensin II–angiotensin AT(1) receptor pathway contributes to the pathophysiology of ARDS, whereas activation of the ACE-2–angiotensin(1-7)-angiotensin AT(2) receptor and the ACE-2–angiotensin(1-7)–Mas receptor pathways have been shown to be protective. Here we propose and discuss therapeutic considerations how to increase soluble ACE-2 in plasma in order for ACE-2 to capture and thereby inactivate SARS-CoV-2. This could be achieved by administering recombinant soluble ACE-2. We also discuss why and how ACEIs and ARBs provide cardiovascular, renal and also pulmonary protection in SARS-CoV-2- associated ARDS. Discontinuing these medications in COVID-19 patients may therefore potentially be harmful.


id: cord-291146-f3e5ynhu
author: Sarangarajan, Rangaprasad
date: 2020-09-08
txt: ./txt/cord-291146-f3e5ynhu.txt
cache: ./cache/cord-291146-f3e5ynhu.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pubmed/32901433/
doi: 10.1007/s40615-020-00853-0
summary:
  The specificity of hypertension and cardiovascular disease as underlying causes for severity of COVID-19 infection, the inherent role of ACE-mediated generation of Ang-II and downstream signalling to potentially exacerbate inflammation and organ damage along with genotypic impact on ACE status provide compelling support of the use of ACE-I and ARBs in the clinical management of patient with positive diagnosis of COVID-19. The significant genetic, scientific and clinical data supporting a potential role for increased ACE levels and associated Ang-II effect in target organs provides compelling argument for use of ACE-I and ARBs in the clinical management of patients with COVID-19 infections to improve outcomes. In summary, this study describes the biological relevance of genetic polymorphism of ACE deletion with higher prevalence in certain ethnic populations including African Americans in context of COVID-19 infection and rationale for the use of ACE-I/ARBs for therapeutic management of severity of morbidity and improving outcomes associated with COVID-19.

title:
  Ethnic Prevalence of Angiotensin-Converting Enzyme Deletion (D) Polymorphism and COVID-19 Risk: Rationale for Use of Angiotensin-Converting Enzyme Inhibitors/Angiotensin Receptor Blockers

abstract:
  RATIONALE: Hypertension, obesity and diabetes are major risk factors associated with morbidities underlying COVID-19 infections. Regression analysis correlated presence of ACE insertion/deletion (I/D) polymorphism to COVID-19 incidence and mortality. Furthermore, COVID-19 prevalence correlated to allele frequency of angiotensin-converting enzyme (ACE) deletion (D) polymorphism within the European population. OBJECTIVE: Homozygous ACE deletion polymorphism is associated with increase in ACE and angiotensin II (Ang-II), sustained levels can result in inflammation, fibrosis and organ damage. The ACE DD polymorphism is also associated with hypertension, acute respiratory distress and diabetic nephropathy, all considered high risk for COVID-19 infection and outcomes. The study objective was to describe a biological framework associating ethnic prevalence of ACE deletion polymorphism to COVID-19 comorbidities providing rationale for therapeutic utility of ACE-I/ARBs to improve outcomes. METHOD AND RESULTS: The Allele Frequency Database (ALFRED) was queried for frequency of rs4646994 representing ACE I/D polymorphism. In a total of 349 worldwide population samples, frequency of ACE D allele was higher in European, Asian, and Africans cohorts. In the USA, the frequency of ACE D allele was higher in non-Hispanic Black compared with non-Hispanic White and Mexican Americans. CONCLUSION: COVID-19 binding mediated reduction/inactivation of ACE-II can increase ACE/Ang-II signalling pathway and related pathologies. The presence of ACE DD polymorphism with COVID-19 infection likely augments ACE/Ang-II activities, increasing severity of COVID-19 morbidities and impacts outcomes. Thus, ethnic prevalence of ACE DD polymorphism can explain in part the severity of COVID-19 morbidity providing rationale for the use of ACE-I/ARBs to improve outcomes.


id: cord-295041-5vpawtef
title: SARS-CoV-2, an Underestimated Pathogen of the Nervous System
author: Jakhmola, Shweta
date: 2020-09-28
txt: ./txt/cord-295041-5vpawtef.txt
cache: ./cache/cord-295041-5vpawtef.txt
extension: .txt
mime: text/plain
url: https://doi.org/10.1007/s42399-020-00522-7
doi: 10.1007/s42399-020-00522-7
summary:
  Numerous clinical studies have reported neurological symptoms in COVID-19 patients since the spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), apart from the atypical signs of pneumonia. Angiotensin-converting enzyme-2 (ACE-2), a potential receptor for SARS-CoV-2 entry, is expressed on various brain cells and cerebral parts, i.e., subfornical organ, paraventricular nucleus, nucleus of the tractus solitarius, and rostral ventrolateral medulla, as well as in non-cardiovascular areas such as the motor cortex and raphe. The resident CNS cells like astrocytes and microglia also express ACE-2, thus highlighting the vulnerability of the nervous system to SARS-CoV-2 infection. Furthermore, the presence of SARS-CoV-2 in cerebrospinal fluid (CSF) of COVID-19 patients is confirmed through genome sequencing [4] ; however, experimental evidence is needed to validate virusmediated neurological damage. Furthermore, the interaction of SARS-CoV-2 and ACE-2-expressing neuronal/glial cells may facilitate virus entry into the nervous system through different routes.

abstract:
  Numerous clinical studies have reported neurological symptoms in COVID-19 patients since the spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), apart from the atypical signs of pneumonia. Angiotensin-converting enzyme-2 (ACE-2), a potential receptor for SARS-CoV-2 entry, is expressed on various brain cells and cerebral parts, i.e., subfornical organ, paraventricular nucleus, nucleus of the tractus solitarius, and rostral ventrolateral medulla, as well as in non-cardiovascular areas such as the motor cortex and raphe. The resident CNS cells like astrocytes and microglia also express ACE-2, thus highlighting the vulnerability of the nervous system to SARS-CoV-2 infection. Additionally, transmembrane serine protease 2 (TMPRSS2) and furin facilitate virus entry into the host. Besides, the probable routes of virus entry into the nervous system include the hematogenic pathway, through the vagus, the olfactory nerve, or the enteric nervous system. However, the trajectory of SARS-CoV-2 to the brain needs investigation. Furthermore, a Th17-mediated cytokine storm is seen in COVID-19 cases with higher levels of IL-1β/2/7/8/9/10/17, GM-CSF, IFN-γ, TNF-α, CXCL-10, MCP1, and MIP1α/β. Some cytokines can cross the blood-brain barrier and activate the brain’s immune cells to produce neural cytokines, leading to neuronal dysfunctions. Nonetheless, most of the neurological conditions developed due to viral infections may not have effective and registered treatments. Although, some antivirals may inhibit the virus-mediated pathogenesis and prove to be suitable in COVID-19 treatment. Therefore, clinicians’ and researchers’ collective expertise may unravel the potential of SARS-CoV-2 infection to prevent short-term and long-term CNS damage.


id: cord-296683-fjn29oal
title: Oral submucous fibrosis and COVID-19: Perspective on comorbidity
author: Sarode, Sachin C
date: 2020-05-21
txt: ./txt/cord-296683-fjn29oal.txt
cache: ./cache/cord-296683-fjn29oal.txt
extension: .txt
mime: text/plain
url: https://doi.org/10.1016/j.oraloncology.2020.104811
doi: 10.1016/j.oraloncology.2020.104811
abstract: nan
summary:
  Novel Corona Virus infection (COVID-19) is a highly infective disease with rapid global spread since January 2020 and was declared as pandemic by World Health Organization. 1 Angiotensin Converting Enzyme 2 (ACE 2), present on the cell surfaces of some important organs, has been identified as target receptor for COVID-19 virus entry into the host cells. 3 In addition, ACE 2 has been reported to be present at various locations in the oral cavity and hence, oral cavity is considered as a potential site for the COVID 19 virus. 8 Thus, the less availability of ACE 2 in the oral cavity might have compromised the binding of COVID 19 virus. The other way round, if OSMF patient is affected with COVID-19, then it may cause further exhaustion of ACE 2. As ACE 2 is the binding site for COVID-19, it may compromise the infectivity of the virus.


id: cord-298515-5n7hxhbg
title: Hyperoxia downregulates angiotensin-converting enzyme-2 in human fetal lung fibroblasts
author: Oarhe, Chinyere I.
date: 2015-02-09
txt: ./txt/cord-298515-5n7hxhbg.txt
cache: ./cache/cord-298515-5n7hxhbg.txt
extension: .txt
mime: text/plain
url: https://doi.org/10.1038/pr.2015.27
doi: 10.1038/pr.2015.27
summary:
  We report here the findings that ACE-2 protein and enzyme activity are severely decreased by hyperoxia in human fetal lung fibroblast cultures. Figure 6 shows that the treatment of hyperoxia followed by normoxic recovery significantly increased ADAM17/TACE immunoreactive protein by threefold in the IMR90 cells (P < 0.05). IMR90 cells were exposed to hyperoxic or normoxic gas as described in Figure 1 (with recovery), but in the presence or absence of the ADAM17/ TACE inhibitor TAPI-2. IMR90 cells were exposed to hyperoxic or normoxic gas as described in Figure 1 (with recovery), but in the presence or absence of the ADAM17/ TACE inhibitor TAPI-2. IMR90 cells were exposed to hyperoxic or normoxic gas as described in Figure 1 (with recovery), then were recovered for western blotting of ADAM17/TACE as described in Materials and Methods.

abstract:
  BACKGROUND: Angiotensin (ANG) II is involved in experimental hyperoxia-induced lung fibrosis. Angiotensin-converting enzyme-2 (ACE-2) degrades ANG II and is thus protective, but is downregulated in adult human and experimental lung fibrosis. Hyperoxia is a known cause of chronic fibrotic lung disease in neonates, but the role of ACE-2 in neonatal lung fibrosis is unknown. We hypothesized that ACE-2 in human fetal lung cells might be downregulated by hyperoxic gas. METHODS: Fetal human lung fibroblast IMR90 cells were exposed to hyperoxic (95% O(2)/5% CO(2)) or normoxic (21% O(2)/5% CO(2)) gas in vitro. Cells and culture media were recovered separately for assays of ACE-2 enzymatic activity, mRNA, and immunoreactive protein. RESULTS: Hyperoxia decreased ACE-2 immunoreactive protein and enzyme activity in IMR90 cells (both P < 0.01), but did not change ACE-2 mRNA. ACE-2 protein was increased in the cell supernatant, suggesting protease-mediated ectodomain shedding. TAPI-2, an inhibitor of TNF-α−converting enzyme (TACE/ADAM17), prevented both the decrease in cellular ACE-2 and the increase in soluble ACE-2 (both P < 0.05). CONCLUSION: These data show that ACE-2 is expressed in fetal human lung fibroblasts but is significantly decreased by hyperoxic gas. They also suggest that hyperoxia decreases ACE-2 through a shedding mechanism mediated by ADAM17/TACE. SUPPLEMENTARY INFORMATION: The online version of this article (doi:10.1038/pr.2015.27) contains supplementary material, which is available to authorized users.


id: cord-300850-59j1m2tm
author: Peron, Jean Pierre Schatzmann
date: 2020-05-11
txt: ./txt/cord-300850-59j1m2tm.txt
cache: ./cache/cord-300850-59j1m2tm.txt
extension: .txt
mime: text/plain
url: https://doi.org/10.6061/clinics/2020/e1912
doi: 10.6061/clinics/2020/e1912
summary:
  Toward this, we raise two main points, i) increased ACE-2 expression in pulmonary and heart tissues in users of chronic angiotensin 1 receptor (AT1R) blockers; and ii) antibody-dependent enhancement (ADE) after previous exposure to other circulating coronaviruses. Toward this, we raise two main points of discussion, i) the increased angiotensin-converting enzyme-2 (ACE-2) expression in pulmonary and heart tissues of hypertensive patients with chronic use of AT1R blockers and ii) antibody-dependent enhancement (ADE) after previous exposure to other circulating coronaviruses. SARS-CoV-2 spike proteins bind to angiotensin-converting enzyme-2 (ACE-2), which is expressed in the epithelial cells of the lungs (8, 9) . We believe that i) increased expression of ACE-2 in hypertensive patients being treated with ACE inhibitors and AT1R blockers and ii) previous exposure to circulating coronaviruses with low neutralizing capacity to SARS-CoV-2 may greatly contribute to the increased susceptibility of the elderly patients to COVID-19.

title:
  Susceptibility of the Elderly to SARS-CoV-2 Infection: ACE-2 Overexpression, Shedding, and Antibody-dependent Enhancement (ADE)

abstract:
  The world is currently facing a serious SARS-CoV-2 infection pandemic. This virus is a new isolate of coronavirus, and the current infection crisis has surpassed the SARS and MERS epidemics that occurred in 2002 and 2013, respectively. SARS-CoV-2 has currently infected more than 142,000 people, causing 5,000 deaths and spreading across more than 130 countries worldwide. The spreading capacity of the virus clearly demonstrates the potential threat of respiratory viruses to human health, thereby reiterating to the governments around the world that preventive health policies and scientific research are pivotal to overcoming the crisis. Coronavirus disease (COVID-19) causes flu-like symptoms in most cases. However, approximately 15% of the patients need hospitalization, and 5% require assisted ventilation, depending on the cohorts studied. What is intriguing, however, is the higher susceptibility of the elderly, especially individuals who are older than 60 years of age, and have comorbidities, including hypertension, diabetes, and heart disease. In fact, the death rate in this group may be up to 10-12%. Interestingly, children are somehow less susceptible and are not considered as a risk group. Therefore, in this review, we discuss some possible molecular and cellular mechanisms by virtue of which the elderly subjects may be more susceptible to severe COVID-19. Toward this, we raise two main points, i) increased ACE-2 expression in pulmonary and heart tissues in users of chronic angiotensin 1 receptor (AT1R) blockers; and ii) antibody-dependent enhancement (ADE) after previous exposure to other circulating coronaviruses. We believe that these points are pivotal for a better understanding of the pathogenesis of severe COVID-19, and must be carefully addressed by physicians and scientists in the field.


id: cord-301546-yck1t3pp
author: Kozaki, Toshinori
date: 2007-12-28
txt: ./txt/cord-301546-yck1t3pp.txt
cache: ./cache/cord-301546-yck1t3pp.txt
extension: .txt
mime: text/plain
url: https://doi.org/10.1002/arch.20229
doi: 10.1002/arch.20229
summary:
  title: Comparison of two acetylcholinesterase gene cDNAs of the lesser mealworm, Alphitobius diaperinus, in insecticide susceptible and resistant strains Two cDNAs encoding different acetylcholinesterase (AChE) genes (AdAce1 and AdAce2) were sequenced and analyzed from the lesser mealworm, Alphitobius diaperinus. Partial cDNA sequences of the Alphitobius Ace genes were compared between two tetrachlorvinphos resistant (Kennebec and Waycross) and one susceptible strain of beetles. The alignment of this gene with the Drosophila Ace paralogous AChEs showed that, as expected for an insecticide-susceptible strain, beetles from the Denmark-S strain had an organophosphate and carbamate sensitive type. The Drosophila Ace orthologous gene, AdAce1, was sequenced from two susceptible Denmark-S, four Waycross (tetrachlorvinphos-resistant), and two Kennebec (tetrachlorvinphos-resistant) adults. diaperinus is not due to mutations in the Ace genes (i.e., is not an altered acetylcholinesterase).Alignments of the deduced amino acid sequences from the Drosophila Ace orthologous and paralogous genes in Coleoptera are shown in Figures 4 and 5, respectively.

title:
  Comparison of two acetylcholinesterase gene cDNAs of the lesser mealworm, Alphitobius diaperinus, in insecticide susceptible and resistant strains

abstract:
  Two cDNAs encoding different acetylcholinesterase (AChE) genes (AdAce1 and AdAce2) were sequenced and analyzed from the lesser mealworm, Alphitobius diaperinus. Both AdAce1 and AdAce2 were highly similar (95 and 93% amino acid identity, respectively) with the Ace genes of Tribolium castaneum. Both AdAce1 and AdAce2 have the conserved residues characteristic of AChE (catalytic triad, intra‐disulfide bonds, and so on). Partial cDNA sequences of the Alphitobius Ace genes were compared between two tetrachlorvinphos resistant (Kennebec and Waycross) and one susceptible strain of beetles. Several single nucleotide polymorphisms (SNPs) were detected, but only one non‐synonymous mutation was found (A271S in AdAce2). No SNPs were exclusively found in the resistant strains, the A271S mutation does not correspond to any mutations previously reported to alter sensitivity of AChE to organophosphates or carbamates, and the A271S was found only as a heterozygote in one individual from one of the resistant A. diaperinus strains. This suggests that tetrachlorvinphos resistance in the Kennebec and Waycross strains of A. diaperinus is not due to mutations in either AChE gene. The sequences of AdAce1 and AdAce2 provide new information about the evolution of these important genes in insects. Arch Insect Biochem Physiol. © 2007 Wiley‐Liss, Inc.


id: cord-302316-raf5rlkq
title: COVID‐19: From pathogenesis models to the first drug trials
author: Brüssow, Harald
date: 2020-06-23
txt: ./txt/cord-302316-raf5rlkq.txt
cache: ./cache/cord-302316-raf5rlkq.txt
extension: .txt
mime: text/plain
url: https://doi.org/10.1111/1751-7915.13611
doi: 10.1111/1751-7915.13611
summary:
  US researchers studied the viral and cellular transcriptional response upon infection of cell cultures and in animal models with different respiratory viruses including influenza A virus and SARS-CoV-2. A French study randomizing 181 COVID-19 patients with pneumonia on hydroxychloroquine or placebo, observed, however, no significant effect of treatment on transfer to ICU, mortality, or in the prevention of development of acute respiratory distress syndrome (Mah evas et al., 2020). A total of 86 COVID-19 cases of patients from China with mild/moderate disease were randomized on the antiviral lopinavir (an inhibitor of HIV protease combined with ritonavir, which prolongs the presence of drugs in the body) or the antiviral arbidol (an influenza virus fusion inhibitor only registered in Russia) or in a control group in a 2:2:1 ratio. Effect of high vs low doses of chloroquine diphosphate as adjunctive therapy for patients hospitalized with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection: a randomized clinical trial

abstract:
  The number of people infected with SARS‐CoV‐2, and sadly dying from COVID‐19, has exploded, and so the amount of literature on the novel coronavirus and the disease it causes has increased proportionately. The case numbers in some countries are beyond the epidemic peak, but the uncertainty about a second wave keeps politicians and societies under pressure. Appropriate decision‐making and winning support from the population depends on precise scientific information rather than leaving the field to scaremongers of all proveniences. This mini‐review is an update of earlier reports (Brüssow, Microb Biotechnol 2020a;13:607; Brüssow, Microb Biotechnol 2020b; https://doi.org/10.1111/1751-7915.13592).


id: cord-304742-ytf2ilw4
author: Albini, Adriana
date: 2020-07-14
txt: ./txt/cord-304742-ytf2ilw4.txt
cache: ./cache/cord-304742-ytf2ilw4.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pubmed/32666177/
doi: 10.1007/s11739-020-02436-7
abstract: nan
summary:
  The transmembrane protease serine 2 TMPRSS2, an androgendependent enzyme, acts in reinforcing the ACE-2 receptor activity in allowing cell entry to a number of viral pathogens as well as to SARS-CoV-2 as reported in our Point of View [2] . Yet in trisomy 21 individuals a TMPRSS2 protease overexpression has been documented, as mentioned in the comment of Dr De Cauwer [1] , with this leading to an increased viral infection''s rate of susceptible host''s cells and tissues. In conclusion, the interesting comment by Dr De Cauwer points out the complex interactions between ACE-2 and TMPRSS2 with reference to the clinical course of CoViD-19 as well as to SARS-CoV-2 infection''s pathogenic evolution and severity degree in given population segments of infected individuals, like male individuals and Down syndromeaffected patients [1] . The SARS-CoV-2 receptor, ACE-2, is expressed on many different cell types: implications for ACEinhibitor-and angiotensin II receptor blocker-based cardiovascular therapies: comment The SARS-CoV-2 receptor, ACE-2, is expressed on many different cell types: implications for ACE-inhibitor-and angiotensin II receptor blocker-based cardiovascular therapies

title:
  The SARS-CoV-2 receptor, ACE-2, is expressed on many different cell types: implications for ACE-inhibitor- and angiotensin II receptor blocker-based antihypertensive therapies—reply


id: cord-306739-4lokd97u
title: Sind ACE-Hemmer eher negativ oder doch von Vorteil bei COVID-19?
author: Gesierich, Wolfgang
date: 2020-07-14
txt: ./txt/cord-306739-4lokd97u.txt
cache: ./cache/cord-306739-4lokd97u.txt
extension: .txt
mime: text/plain
url: https://doi.org/10.1007/s15033-020-1857-7
doi: 10.1007/s15033-020-1857-7
abstract: nan
summary:
  Bei COVID-19 wird neben der meist vorherrschenden akuten Lungenschädigung (ARDS) auch eine relevante Rate an myokardialen Schäden (Anstieg von Troponin) und akutem Nierenversagen beobachtet. Bereits aus der Zeit von SARS gibt es experimentelle Daten, die eine entsprechende Interaktion zwischen SARS-CoV-1 und dem RAAS belegen [2] . Ebenso gibt es experimentelle Studien, die einen krankheitsfördernden Effekt einer RAAS-Aktivierung bei ARDS nicht infektiöser Genese nahelegen [3] . Die dargestellten britischen Daten dürfen als erstes Signal gewertet werden, dass ACE-Hemmer auch bei COVID-19 einen günstigen Effekt auf den Krankheitsverlauf haben könnten. Weitere klinische Studien sind also dringend erforderlich, bevor den ACE-Hemmern ein therapeutischer Effekt bei COVID-19 zugeschrieben werden kann. Vorerst darf folgendes Fazit gezogen werden, das von nationalen und internationalen Fachgesellschaften unterstützt wird: Eine vorbestehende Therapie mit einem ACE-Hemmer, die für Patienten mit kardiovaskulären Erkrankungen und Diabetes mellitus einen relevanten organprotektiven und damit prognostischen Wert hat, sollte in der aktuellen Pandemie-Situation und insbesondere bei Diagnose einer SARS-CoV-2-Infektion nicht abgesetzt werden.


id: cord-306755-9q1mawfs
author: Rivière, Guillaume
date: 2007-09-01
txt: ./txt/cord-306755-9q1mawfs.txt
cache: ./cache/cord-306755-9q1mawfs.txt
extension: .txt
mime: text/plain
url: https://api.elsevier.com/content/article/pii/S0378111907002521
doi: 10.1016/j.gene.2007.05.010
summary:
  Interestingly, in silico databank analysis revealed that bacterial DNA sequences could encode putative ACE-like proteins, strikingly similar to vertebrates'' enzymes. Interestingly, and though in silico evidence suggest the presence of a two-domain ACE-related protein in mosquitoes (Burnham et al., 2005) , all the cloned genes encode soluble, single active site enzymes (Tatei et al., 1995; Taylor et al., 1996; Wijffels et al., 1996) . The protein encoded by this gene, referred to as XcACE (Xanthomonas citri angiotensin-converting enzyme), is a 672 amino-acid protein. Key active site residues such as the zinc-binding motif, His 513 and Tyr 526 (tACE numbering) are conserved in XcACE and many other ACE-like enzymes. However, in line with the assay results, the non-conserved active site residues are neither identical to the C-or N-domain of human ACE, and are the presumed cause of the different substrate selectivity and inhibition profile of XcACE. Functional conservation of the active sites of human and Drosophila angiotensin I-converting enzyme

title:
  Characterization of the first angiotensin-converting like enzyme in bacteria: Ancestor ACE is already active

abstract:
  Angiotensin-converting enzyme (ACE) is a metallopeptidase that converts angiotensin I into angiotensin II. ACE is crucial in the control of cardiovascular and renal homeostasis and fertility in mammals. In vertebrates, both transmembrane and soluble ACE, containing one or two active sites, have been characterized. So far, only soluble, single domain ACEs from invertebrates have been cloned, and these have been implicated in reproduction in insects. Furthermore, an ACE-related carboxypeptidase was recently characterized in Leishmania, a unicellular eukaryote, suggesting the existence of ACE in more distant organisms. Interestingly, in silico databank analysis revealed that bacterial DNA sequences could encode putative ACE-like proteins, strikingly similar to vertebrates' enzymes. To gain more insight into the bacterial enzymes, we cloned the putative ACE from the phytopathogenic bacterium, Xanthomonas axonopodis pv. citri, named XcACE. The 2 kb open reading frame encodes a 672-amino-acid soluble protein containing a single active site. In vitro expression and biochemical characterization revealed that XcACE is a functional 72 kDa dipeptidyl-carboxypeptidase. As in mammals, this metalloprotease hydrolyses angiotensin I into angiotensin II. XcACE is sensitive to ACE inhibitors and chloride ions concentration. Variations in the active site residues, highlighted by structural modelling, can account for the different substrate selectivity and inhibition profile compared to human ACE. XcACE characterization demonstrates that ACE is an ancestral enzyme, provoking questions about its appearance and structure/activity specialisation during the course of evolution.


id: cord-311099-59pnm4fn
title: Liver disease and the renin–angiotensin system: Recent discoveries and clinical implications
author: Lubel, John S
date: 2008-06-28
txt: ./txt/cord-311099-59pnm4fn.txt
cache: ./cache/cord-311099-59pnm4fn.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pubmed/18557800/
doi: 10.1111/j.1440-1746.2008.05461.x
summary:
  Drug therapies targeting the RAS by inhibiting Ang II formation (ACE inhibitors) or binding to its receptor (angiotensin receptor blockers) are now in widespread clinical use and have been shown to reduce tissue injury and fibrosis in cardiac and renal disease independently of their effects on blood pressure. Interestingly, ACE inhibitors and angiotensin receptor blockers increase Ang‐(1–7) production and it has been proposed that some of the beneficial effects of these drugs are mediated through upregulation of Ang‐(1–7) rather than inhibition of Ang II production or receptor binding. 42 A great deal of evidence supporting the role of the RAS in hepatic fibrosis has come from animal studies using ACE inhibitors and angiotensin receptor blockers (ARB). A pilot study examining the effects of 6 months of losartan treatment on liver fibrosis in chronic hepatitis C demonstrated a significant decrease in fibrosis stage in the treated group compared to control patients.

abstract:
  The renin–angiotensin system (RAS) is a key regulator of vascular resistance, sodium and water homeostasis and the response to tissue injury. Historically, angiotensin II (Ang II) was thought to be the primary effector peptide of this system. Ang II is produced predominantly by the effect of angiotensin converting enzyme (ACE) on angiotensin I (Ang I). Ang II acts mainly through the angiotensin II type‐1 receptor (AT(1)) and, together with ACE, these components represent the ‘classical’ axis of the RAS. Drug therapies targeting the RAS by inhibiting Ang II formation (ACE inhibitors) or binding to its receptor (angiotensin receptor blockers) are now in widespread clinical use and have been shown to reduce tissue injury and fibrosis in cardiac and renal disease independently of their effects on blood pressure. In 2000, two groups using different methodologies identified a homolog of ACE, called ACE2, which cleaves Ang II to form the biologically active heptapeptide, Ang‐(1–7). Conceptually, ACE2, Ang‐(1–7), and its putative receptor, the mas receptor represent an ‘alternative’ axis of the RAS capable of opposing the often deleterious actions of Ang II. Interestingly, ACE inhibitors and angiotensin receptor blockers increase Ang‐(1–7) production and it has been proposed that some of the beneficial effects of these drugs are mediated through upregulation of Ang‐(1–7) rather than inhibition of Ang II production or receptor binding. The present review focuses on the novel components and pathways of the RAS with particular reference to their potential contribution towards the pathophysiology of liver disease.


id: cord-314868-ei2b8oqn
author: Leung, J. M.
date: 2020-03-23
txt: ./txt/cord-314868-ei2b8oqn.txt
cache: ./cache/cord-314868-ei2b8oqn.txt
extension: .txt
mime: text/plain
url: http://medrxiv.org/cgi/content/short/2020.03.18.20038455v1?rss=1
doi: 10.1101/2020.03.18.20038455
summary:
  Because individuals with chronic obstructive pulmonary disease (COPD) are at increased risk of severe COVID19, we determined whether ACE2 expression in the lower airways was related to COPD and cigarette smoking. Results: In the discovery cohort (n=42 participants), we found that ACE2 expression levels were increased by 48% in the airways of COPD compared with non-COPD subjects (COPD=2.52 (0.66) log2 counts per million reads (CPM) versus non-COPD= 1.70 (0.51) CPM , p=.000762). In summary, active cigarette smoking and COPD up-regulate ACE-2 expression in lower airways, which in part may explain the increased risk of severe COVID-19 in these sub-populations. The P-value was obtained from the robust linear model Abbreviations: ACE-2, angiotensin converting enzyme II; COPD, chronic obstructive pulmonary disease; CPM, counts per million reads . 18.20038455 doi: medRxiv preprint Abbreviations: ACE-2, angiotensin converting enzyme II; COPD, chronic obstructive pulmonary disease; CPM, counts per million reads ACE-2 gene expression in airway epithelia is inversely related to FEV1% predicted (p=0.0348)

title:
  ACE-2 Expression in the Small Airway Epithelia of Smokers and COPD Patients: Implications for COVID-19

abstract:
  Introduction: Coronavirus disease 2019 (COVID-19) is a respiratory infection caused by the severe acute respiratory syndrome coronavirus2 (SARSCoV-2). This virus uses the angiotensin converting enzyme II (ACE2) as the cellular entry receptor to infect the lower respiratory tract. Because individuals with chronic obstructive pulmonary disease (COPD) are at increased risk of severe COVID19, we determined whether ACE2 expression in the lower airways was related to COPD and cigarette smoking. Methods: Using RNAseq, we determined gene expression levels in bronchial epithelia obtained from cytologic brushings of 6th to 8th generation airways in individuals with and without COPD. We externally validated these results from two additional independent cohorts, which used microarray technologies to measure gene expression levels from 6th to 12th generation airways. Results: In the discovery cohort (n=42 participants), we found that ACE2 expression levels were increased by 48% in the airways of COPD compared with non-COPD subjects (COPD=2.52 (0.66) log2 counts per million reads (CPM) versus non-COPD= 1.70 (0.51) CPM , p=.000762). There was a significant inverse relationship between ACE2 gene expression and FEV1% of predicted (r=negative 0.24; p=0.035). Current smoking also significantly increased ACE2 expression levels compared with never smokers (never current smokers=2.77 (90.91) CPM versus smokers=1.78 (0.39) CPM, p=0.024). These findings were replicated in the two external cohorts. Conclusions: ACE2 expression in lower airways is increased in patients with COPD and with current smoking. These data suggest that these two subgroups are at increased risk of serious COVID19 infection and highlight the importance of smoking cessation in reducing the risk.


id: cord-315754-dq2empne
author: Hasan, Anwarul
date: 2020-04-22
txt: ./txt/cord-315754-dq2empne.txt
cache: ./cache/cord-315754-dq2empne.txt
extension: .txt
mime: text/plain
url: https://doi.org/10.1080/07391102.2020.1754293
doi: 10.1080/07391102.2020.1754293
summary:
  Angiotensin-converting enzyme-2 (ACE-2) is one of the most important receptors on the cell membrane of the host cells (HCs) which its interaction with spike protein (SP) with a furin-cleavage site results in the SARS-CoV-2 invasion. Genomic analysis of the new CoV has shown that its SP differs from that of other viruses (Du et al., 2017; Li, 2016) , indicating that the protein has a site activated by a HC enzyme called furin (Millet & Whittaker, 2015) (Figure 1 ). The furin activation site (FAS) makes the new CoV much different in cell entry than SARS, and probably affects the stability of the virus and, consequently, the transmission process (Li et al., 2015; Millet & Whittaker, 2014; Yamada & Liu, 2009) . A hexapeptide of the receptor-binding domain of SARS corona virus spike protein blocks viral entry into host cells via the human receptor ACE2

title:
  A review on the cleavage priming of the spike protein on coronavirus by angiotensin-converting enzyme-2 and furin

abstract:
  The widespread antigenic changes lead to the emergence of a new type of coronavirus (CoV) called as severe acute respiratory syndrome (SARS)-CoV-2 that is immunologically different from the previous circulating species. Angiotensin-converting enzyme-2 (ACE-2) is one of the most important receptors on the cell membrane of the host cells (HCs) which its interaction with spike protein (SP) with a furin-cleavage site results in the SARS-CoV-2 invasion. Hence, in this review, we presented an overview on the interaction of ACE-2 and furin with SP. As several kinds of CoVs, from various genera, have at their S1/S2 binding site a preserved site, we further surveyed the role of furin cleavage site (FCS) on the life cycle of the CoV. Furthermore, we discussed that the small molecular inhibitors can limit the interaction of ACE-2 and furin with SP and can be used as potential therapeutic platforms to combat the spreading CoV epidemic. Finally, some ongoing challenges and future prospects for the development of potential drugs to promote targeting specific activities of the CoV were reviewed. In conclusion, this review may pave the way for providing useful information about different compounds involved in improving the effectiveness of CoV vaccine or drugs with minimum toxicity against human health. Communicated by Ramaswamy H. Sarma


id: cord-317878-bqpj0ey0
author: Czick, Maureen
date: 2020-09-11
txt: ./txt/cord-317878-bqpj0ey0.txt
cache: ./cache/cord-317878-bqpj0ey0.txt
extension: .txt
mime: text/plain
url: https://doi.org/10.2147/dmso.s265518
doi: 10.2147/dmso.s265518
summary:
  Silent hypoxia, atypical acute respiratory distress syndrome (ARDS), stroke, olfactory loss, myocarditis, and increased mortality rates in the elderly, in men, in African-Americans, and in patients with obesity, diabetes, and cancer—all bear the fingerprints of the renin-angiotensin system (RAS) imbalance, suggesting that RAS is the common culprit. Subpopulations manifesting higher rates of COVID-19 mortality-including hypertensives, the elderly, the obese, diabetics, men, and African-Americans-correlate with preexisting RAS imbalance, with ACE overactivity and/or ACE2 underactivity priming these patients for more severe COVID-19 outcomes. 159 Males generally have higher levels of RAS than premenopausal females, 160 perhaps explaining why male hypertensive rats show a greater blood pressure decrease with ACEIs. 161 Estrogen downregulates the expression of the AT1 gene 162, 163 and suppresses both ROS production in vascular smooth muscle and the enzymatic activity of ACE.

title:
  COVID’s Razor: RAS Imbalance, the Common Denominator Across Disparate, Unexpected Aspects of COVID-19

abstract:
  A modern iteration of Occam’s Razor posits that “the simplest explanation is usually correct.” Coronavirus Disease 2019 involves widespread organ damage and uneven mortality demographics, deemed unexpected from what was originally thought to be “a straightforward respiratory virus.” The simplest explanation is that both the expected and unexpected aspects of COVID-19 share a common mechanism. Silent hypoxia, atypical acute respiratory distress syndrome (ARDS), stroke, olfactory loss, myocarditis, and increased mortality rates in the elderly, in men, in African-Americans, and in patients with obesity, diabetes, and cancer—all bear the fingerprints of the renin-angiotensin system (RAS) imbalance, suggesting that RAS is the common culprit. This article examines what RAS is and how it works, then from that baseline, the article presents the evidence suggesting RAS involvement in the disparate manifestations of COVID-19. Understanding the deeper workings of RAS helps one make sense of severe COVID-19. In addition, recognizing the role of RAS imbalance suggests potential routes to mitigate COVID-19 severity.


id: cord-318327-9sh2eksm
author: Garg, M.
date: 2012-01-05
txt: ./txt/cord-318327-9sh2eksm.txt
cache: ./cache/cord-318327-9sh2eksm.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pubmed/22221317/
doi: 10.1111/j.1365-2036.2011.04971.x
summary:
  Animal studies investigating the effects of RAS blockade in a range of conditions including inflammatory bowel disease, functional gut disorders, gastrointestinal malignancy and even intestinal ischaemia have been encouraging to date. Animal studies investigating the effects of RAS blockade in a range of conditions including inflammatory bowel disease, functional gut disorders, gastrointestinal malignancy and even intestinal ischaemia have been encouraging to date. The contemporary view of the RAS has evolved from that of a simple linear pathway involving the conversion of angiotensinogen to angiotensin II (Ang II) via a two-step process facilitated by renin and angiotensin converting enzyme (ACE), to a much more complex system involving homologues of ACE and multiple angiotensin peptides which play supplementary and counter-regulatory roles ( Figure 1 ). Angiotensin converting enzyme inhibition or angiotensin receptor antagonism have been shown to produce a number of beneficial anti-inflammatory effects in rodent models of intestinal inflammation.

title:
  Review article: the pathophysiological roles of the renin–angiotensin system in the gastrointestinal tract

abstract:
  BACKGROUND: The renin‐angiotensin system (RAS) is a homeostatic pathway widely known to regulate cardiovascular and renal physiology; however, little is known about its influence in gastrointestinal tissues. AIM: To elicit the anatomical distribution and physiological significance of the components of the RAS in the gastrointestinal tract. METHODS: An extensive online literature review including Pubmed and Medline. RESULTS: There is evidence for RAS involvement in gastrointestinal physiology and pathophysiology, with all the components required for autonomous regulation identified throughout the gastrointestinal tract. The RAS is implicated in the regulation of glucose, amino acid, fluid and electrolyte absorption and secretion, motility, inflammation, blood flow and possibly malignant disease within the gastrointestinal tract. Animal studies investigating the effects of RAS blockade in a range of conditions including inflammatory bowel disease, functional gut disorders, gastrointestinal malignancy and even intestinal ischaemia have been encouraging to date. Given the ready availability of drugs that modify the RAS and their excellent safety profile, an opportunity exists for investigation of their possible therapeutic role in a variety of human gastrointestinal diseases. CONCLUSIONS: The gastrointestinal renin‐angiotensin system appears to be intricately involved in a number of physiological processes, and provides a possible target for novel investigative and therapeutic approaches.


id: cord-319022-1twsxzcd
author: Desai, Antonio
date: 2020-09-25
txt: ./txt/cord-319022-1twsxzcd.txt
cache: ./cache/cord-319022-1twsxzcd.txt
extension: .txt
mime: text/plain
url: https://doi.org/10.1016/j.ijcard.2020.09.062
doi: 10.1016/j.ijcard.2020.09.062
summary:
  BACKGROUND: There is a great deal of debate about the role of cardiovascular comorbidities and the chronic use of antihypertensive agents (such as ACE-I and ARBs) on mortality on COVID-19 patients. The aim of the study was to evaluate the role of chronic treatment with ACE-I or ARBs and other clinical predictors on in-hospital mortality in a cohort of COVID-19 patients. As for today, there are discordant results regarding the use of either angiotensin converting enzyme inhibitors (ACE-I) or angiotensin II receptor blockers (ARBs) as for their possible impact on COVID-19 mortality. We found that ACE-I, which acts by inhibiting the conversion from angiotensin I to angiotensin II, showed a trend in protecting from mortality from COVID-19 and was significant in delaying mortality as shown by multivariate Cox regression analysis unlike ARBs, which antagonize the effects of angiotensin II on its receptors 2,3 . Association of Inpatient Use of Angiotensin Converting Enzyme Inhibitors and Angiotensin II Receptor Blockers with Mortality Among Patients With Hypertension Hospitalized With COVID-19

title:
  The role of anti-hypertensive treatment, comorbidities and early introduction of LMWH in the setting of COVID-19: A retrospective, observational study in Northern Italy()

abstract:
  BACKGROUND: There is a great deal of debate about the role of cardiovascular comorbidities and the chronic use of antihypertensive agents (such as ACE-I and ARBs) on mortality on COVID-19 patients. Of note, ACE2 is responsible for the host cell entry of the virus. METHOD: We extracted data on 575 consecutive patients with laboratory-confirmed SARS-CoV-2 infection admitted to the Emergency Department (ED) of Humanitas Center, between February 21 and April 14, 2020. The aim of the study was to evaluate the role of chronic treatment with ACE-I or ARBs and other clinical predictors on in-hospital mortality in a cohort of COVID-19 patients. RESULTS: Multivariate analysis showed that a chronic intake of ACE-I was associated with a trend in reduction of mortality (OR: 0.53; 95% CI: 0.27–1.03; p = 0.06). Increased age (ORs ranging from 3.4 to 25.2 and to 39.5 for 60–70, 70–80 and > 80 years vs < 60) and cardiovascular comorbidities (OR: 1.90; 95% CI: 1.1–3.3; p = 0.02) were confirmed as important risk factors for COVID-19 mortality. Timely treatment with low-molecular-weight heparin (LMWH) in ED was found to be protective (OR: 0.36; 95% CI: 0.21–0.62; p < 0.0001). CONCLUSIONS: This study can contribute to understand the reasons behind the high mortality rate of patients in Lombardy, a region which accounts for >50% of total Italian deaths. Based on our findings, we support that daily intake of antihypertensive medications in the setting of COVID-19 should not be discontinued and that a timely LMWH administration in ED has shown to decrease in-hospital mortality.


id: cord-322966-o65fo853
author: Arnold, Ruth H.
date: 2020-05-25
txt: ./txt/cord-322966-o65fo853.txt
cache: ./cache/cord-322966-o65fo853.txt
extension: .txt
mime: text/plain
url: https://api.elsevier.com/content/article/pii/S1443950620301451
doi: 10.1016/j.hlc.2020.05.004
summary:
  title: COVID-19 – Does This Disease Kill Due to Imbalance of the Renin Angiotensin System (RAS) Caused by Genetic and Gender Differences in the Response to Viral ACE 2 Attacks? ABSTRACT Debate continues in the medical literature on the role of the renin angiotensin system (RAS) in Coronavirus disease 2019 (COVID-19) pathophysiology and the implications for the use of cardiovascular drugs acting on the RAS. Debate continues in the medical literature on the role of the renin angiotensin system (RAS) in Coronavirus disease 2019 (COVID19) pathophysiology and the implications for the use of cardiovascular drugs acting on the RAS. Debate has arisen due to the finding that underlying cardiovascular disease and hypertension are associated with significantly increased risk of hospitalisation and death in COVID-19 [1, 2] , in addition to the viral receptor being angiotensin-converting enzyme-2 (ACE-2) [3 -5] . Association of renin-angiotensin system inhibitorswith severity or risk of death in patients with hypertension hospitalised for coronavirus disease 19 (COVID-19) infection in Wuhan, China

title:
  COVID-19 – Does This Disease Kill Due to Imbalance of the Renin Angiotensin System (RAS) Caused by Genetic and Gender Differences in the Response to Viral ACE 2 Attacks?

abstract:
  ABSTRACT Debate continues in the medical literature on the role of the renin angiotensin system (RAS) in Coronavirus disease 2019 (COVID-19) pathophysiology and the implications for the use of cardiovascular drugs acting on the RAS. Could these drugs – which include angiotensin converting enzyme inhibitors (ACEIs) and angiotensin receptors blockers (ARBs) – be harmful or potential key therapeutic agents in COVID-19?


id: cord-326405-3446eyi3
title: Angiotensin-converting enzyme 2: Possible role in hypertension and kidney disease
author: Wysocki, Jan
date: 2008-02-07
txt: ./txt/cord-326405-3446eyi3.txt
cache: ./cache/cord-326405-3446eyi3.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pubmed/18367030/
doi: 10.1007/s11906-008-0014-1
summary:
  The high catalytic efficiency of ACE2 for the generation of angiotensin (ANG)-1-7 from ANG II suggests an important role of ACE2 in preventing ANG II accumulation, while at the same time enhancing ANG-1-7 formation. [41] , primarily describing an Ace2 knockout and its associated cardiac pathology, also reported that ACE2 was reduced at the gene and protein level in kidneys from three separate rat models of spontaneous and diet-induced hypertension. Investigating the role of ACE2 in those two prevalent diseases and whether its effects are mediated by ANG II or ANG-(1-7) and other biologically active peptides, which are also substrates of ACE2, opens the way for developing new therapeutic targets in hypertension. ACE2 inhibition worsens glomerular injury in association with increased ACE expression in streptozotocin-induced diabetic mice Also, pharmacologic ACE2 inhibition was associated with increased albuminuria, suggesting a role of glomerular ACE2 in diabetic kidney injury

abstract:
  The discovery of angiotensin-converting enzyme (ACE) 2 adds a new level of complexity to the understanding of the renin-angiotensin system. The high catalytic efficiency of ACE2 for the generation of angiotensin (ANG)-1-7 from ANG II suggests an important role of ACE2 in preventing ANG II accumulation, while at the same time enhancing ANG-1-7 formation. ACE and ACE2 may have counterbalancing functions and a regulatory role in fine-tuning the rate at which ANG peptides are formed and degraded. By counterregulating the actions of ACE on ANG II formation, ACE2 may play a role in maintaining a balanced status of the renninangiotensin system. This review focuses on the function of ACE2 and its possible roles in kidney disease and hypertension. Studies using models of ACE2 ablation and the pharmacologic administration of an ACE2 inhibitor suggest that decreased ACE2 activity alone or in combination with increased ACE activity may play a role in both diseases.


id: cord-326820-11sl17ap
title: Is diet partly responsible for differences in COVID-19 death rates between and within countries?
author: Bousquet, Jean
date: 2020-05-27
txt: ./txt/cord-326820-11sl17ap.txt
cache: ./cache/cord-326820-11sl17ap.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pubmed/32499909/
doi: 10.1186/s13601-020-00323-0
summary:
  title: Is diet partly responsible for differences in COVID-19 death rates between and within countries? The low-death rate European countries (e.g. Austria, Baltic States, Czech Republic, Finland, Norway, Poland, Slovakia) have used different quarantine and/or confinement times and methods and none have performed as many early tests as Germany. It seems that some foods largely used in these countries may reduce angiotensin-converting enzyme activity or are anti-oxidants. Among the many possible areas of research, it might be important to understand diet and angiotensin-converting enzyme-2 (ACE2) levels in populations with different COVID-19 death rates since dietary interventions may be of great benefit. Although there are large differences between countries in death rates, the age-dependent severity of COVID-19 is similar between Asian, European and American countries. Identifying whether countries with high or low ACE activity have different death rates would be of great interest in understanding the clinical importance of interventions.

abstract:
  Reported COVID-19 deaths in Germany are relatively low as compared to many European countries. Among the several explanations proposed, an early and large testing of the population was put forward. Most current debates on COVID-19 focus on the differences among countries, but little attention has been given to regional differences and diet. The low-death rate European countries (e.g. Austria, Baltic States, Czech Republic, Finland, Norway, Poland, Slovakia) have used different quarantine and/or confinement times and methods and none have performed as many early tests as Germany. Among other factors that may be significant are the dietary habits. It seems that some foods largely used in these countries may reduce angiotensin-converting enzyme activity or are anti-oxidants. Among the many possible areas of research, it might be important to understand diet and angiotensin-converting enzyme-2 (ACE2) levels in populations with different COVID-19 death rates since dietary interventions may be of great benefit.


id: cord-327697-80msva10
author: Sarı, Cenk
date: 2020-11-09
txt: ./txt/cord-327697-80msva10.txt
cache: ./cache/cord-327697-80msva10.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pubmed/33168943/
doi: 10.1038/s41371-020-00436-w
summary:
  Concern has arisen about the role played in coronavirus disease 2019 (COVID-19) infection by angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs). In the first half of 2020, it was speculated that angiotensinconverting enzyme inhibitors (ACE-i)/angiotensin receptor blockers (ARBs) may make patients more susceptible to COVID-19 disease and lead to worse outcomes. Observational studies have reported that patients taking ACE-i/ARBs treatment are at increased risk of becoming infected with SARS-CoV2 and developing severe forms of COVID-19 disease. The strategy for repeating therapy was the same in all physicians, and the practice of starting new ACE-i/ARBs reported by the cardiologists was statistically different from that of both internal medicine and family medicine/general practitioners (8.0 ± 4 vs 8.0 ± 4 vs 9.0 ± 3, p < 0.05) ( Table 2) . The present survey is the first study to have provided a snapshot showing behaviors of Turkish physicians toward prescribing ACE-i/ARBs treatment during the COVID-19 pandemic.

title:
  The outcomes of the postulated interaction between SARS-CoV-2 and the renin-angiotensin system on the clinician’s attitudes toward hypertension treatment

abstract:
  Concern has arisen about the role played in coronavirus disease 2019 (COVID-19) infection by angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs). This study was designed to assess the practice behaviors of physicians toward hypertension treatment with ACE-i or ARBs during the COVID-19 pandemic. A self-administered survey questionnaire consisting of 26 questions about current hypertension treatment with ACE-i/ ARBs was applied to cardiologists, internists, and family physicians in central and western Turkey, between 01 and 19 May 2020. A total of 460 physicians were approached, and 220 (47.8%) participated in the study. Of the total respondents, 78.7% reported that they had not changed their antihypertensive medication prescribing pattern, 8.6% of clinicians had changed ACE-i/ ARBs medicine of patients during the COVID-19 pandemic and 12.7% of them were undecided. The median (±interquartile range) score indicating general reliance level of physicians in ACE-i/ARBs therapy was 8 ± 4 (range, 1–10). In multiple comparison analyses, the general reliance level in ACE-i/ARBs, reliance level when starting a new ACEi/ARBs and changing behavior in heart failure patients were significantly different with regard to the specialties (p:0.02, p:0.009, p:0.005 respectively). Although most of the physicians found the publications about ACE-i/ ARBs during the COVID-19 pandemic untrustworthy, there were variable levels of knowledge and reliance among different physicians and specialty groups. In general, the ACE-i/ ARBs prescribing habits were not affected by safety concerns during the COVID-19 pandemic in Turkey.


id: cord-330093-asba80bi
title: Smoking, ACE-2 and COVID-19: ongoing controversies
author: Leung, Janice M.
date: 2020-07-16
txt: ./txt/cord-330093-asba80bi.txt
cache: ./cache/cord-330093-asba80bi.txt
extension: .txt
mime: text/plain
url: https://doi.org/10.1183/13993003.01759-2020
doi: 10.1183/13993003.01759-2020
abstract: Smoking increases severity of COVID-19 https://bit.ly/2yWp3jb
summary:
  Both research teams are reporting increased angiotensin-converting enzyme 2 (ACE-2) expression in airways of current smokers and those with COPD, with important implications for coronavirus disease 2019 (COVID-19) patients. Since ACE-2 has been shown to be the main receptor utilised by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) to enter the host cells [2] , the authors conclude that nicotine is a risk factor for COVID-19. Here, we bring to the discussion whether the increased susceptibility and virulence of SARS-CoV-2 via α7-nAChR and the upregulation of small airway ACE-2 expression may also be relevant for those who vape using nicotine-based e-cigarettes. While smoking may not necessarily increase one''s risk for contracting COVID-19, the biological and inflammatory cascade that occurs upon severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection may be particularly devastating for a smoker.


id: cord-332680-zfn81hew
author: Chan, Chieh-Kai
date: 2020-09-10
txt: ./txt/cord-332680-zfn81hew.txt
cache: ./cache/cord-332680-zfn81hew.txt
extension: .txt
mime: text/plain
url: https://doi.org/10.1161/hypertensionaha.120.15989
doi: 10.1161/hypertensionaha.120.15989
summary:
  The following variables were extracted: author, journal, publication year, study design, geographic location, participants'' details (number, study population, age, sex, and comorbidities, including hypertension, diabetes mellitus, heart failure, and chronic kidney disease), use of antihypertensive drugs, such as ACE inhibitors, ARBs, calcium-channel blockers, beta-blockers, diuretics, outcomes (including positive SARS-CoV-2 test results and disease prognosis/severity, if available). The systematic review findings of the 7 high-quality studies (with comparative data on the controls) on SARS-COV-2 infection provide the best available evidence proving that therapy with ACE inhibitors or ARBs is not associated with an increase of positive SARS-CoV-2 test result and the severity of COVID-19 disease or overall population mortality as a whole in case-population and cohort studies. ACE indicates angiotensin-converting enzyme; ARBs, angiotensin receptor blockers; BMI, body mass index; CKD, chronic kidney disease; DM, diabetes mellitus; HTN, hypertension; ICU, intensive care unit; N/A, not applicable; OHA, oral hypoglycemic agents; RAASi, renin-angiotensin-aldosterone system inhibitors; and SARS-CoV-2, severe acute respiratory syndrome coronavirus 2.

title:
  Renin-Angiotensin-Aldosterone System Inhibitors and Risks of Severe Acute Respiratory Syndrome Coronavirus 2 Infection: A Systematic Review and Meta-Analysis

abstract:
  The viral spike coat protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) engages the human ACE (angiotensin-converting enzyme)2 cell surface receptor to infect the host cells. Thus, concerns arose regarding theoretically higher risk for coronavirus disease-19 (COVID-19) in patients taking ACE inhibitors/angiotensin II type 1 receptor antagonists (angiotensin receptor blockers [ARBs]). We systematically assessed case-population and cohort studies from MEDLINE (Ovid), Cochrane Database of Systematic Reviews PubMed, Embase, medRXIV, the World Health Organization database of COVID-19 publications, and ClinicalTrials.gov through June 1, 2020, with planned ongoing surveillance. We rated the certainty of evidence according to Cochrane methods and the GRADE approach. After pooling the adjusted odds ratios from the included studies, no significant increase was noted in the risk of SARS-CoV-2 infection by the use of ACEinhibitors (adjusted odds ratio, 0.95 [95% CI, 0.86–1.05]) or ARBs (adjusted odds ratio, 1.05 [95% CI, 0.97–1.14]). However, the random-effects meta-regression revealed that age may modify the SARS-CoV-2 infection risk in subjects with the use of ARBs (coefficient, −0.006 [95% CI, −0.016 to 0.004]), that is, the use of ARBs, as opposed to ACE inhibitors, specifically augmented the risk of SARS-CoV-2 infection in younger subjects (<60 yearsold). The use of ACE inhibitors might not increase the susceptibility of SARS-CoV-2 infection, severity of disease, and mortality in case-population and cohort studies. Additionally, we discovered for the first time that the use of ARBs, as opposed to ACE inhibitors, specifically augmented the risk of SARS-CoV-2 infection in younger subjects, without obvious effects on COVID-19 outcomes.


id: cord-334490-42gykxdx
title: COVID-19: frequently asked questions to the cardiologist
author: Kammerlander, Andreas A.
date: 2020-07-24
txt: ./txt/cord-334490-42gykxdx.txt
cache: ./cache/cord-334490-42gykxdx.txt
extension: .txt
mime: text/plain
url: https://doi.org/10.1007/s00508-020-01696-9
doi: 10.1007/s00508-020-01696-9
abstract: nan
summary:
  The specific causes of troponin rise in COVID-19 in patients without cardiac conditions, such as acute coronary syndrome (ACS), aortic stenosis, hypertrophic cardiomyopathy, and tachycardia A. Cardiac injury, defined as elevated troponin levels, is frequently observed in patients with COVID-19. The European Association of Percutaneous Cardiovascular Interventions (EAPCI) issued a position statement on invasive management in patients with ACS during the COVID-19 pandemic [19] . The EAPCI recommends that in cases of mild troponin elevation (<2-3 times the upper limit of normal), particularly in older patients with pre-existing cardiac conditions, a work-up for type 1 MI is not indicated, unless strongly indicated by clinical presentation and electrocardiograph (ECG) findings. Association of Cardiac Injury With Mortality in Hospitalized Patients With COVID-19 in Wuhan, China Association of Renin-Angiotensin system inhibitors with severity or risk of death in patients with hypertension hospitalized for Coronavirus disease 2019 (COVID-19) infection in Wuhan, China


id: cord-338417-7kw9lws0
author: Singh, Awadhesh Kumar
date: 2020-04-09
txt: ./txt/cord-338417-7kw9lws0.txt
cache: ./cache/cord-338417-7kw9lws0.txt
extension: .txt
mime: text/plain
url: https://doi.org/10.1016/j.dsx.2020.03.016
doi: 10.1016/j.dsx.2020.03.016
summary:
  RESULTS: From the pooled data of all ten available Chinese studies (n = 2209) that have reported the characteristics of comorbidities in patients with COVID-19, hypertension was present in nearly 21%, followed by diabetes in nearly 11%, and established cardiovascular disease (CVD) in approximately 7% of patients. Emerging data suggests that older COVID-19 patients with other comorbid conditions such as diabetes, hypertension, cardiac and pulmonary disease are in particular more susceptible, compared to general populations and have higher mortality. We have systematically searched the PubMed medical database up till March 27, 2020 using MeSH key words that include Covid-19, coronavirus, hypertension, diabetes, cardiovascular disease, angiotensin receptor blockers, angiotensin converting enzyme inhibitors. Interestingly, in the pooled data from the ten Chinese studies (n ¼ 2209) that have reported the characteristics of comorbidities in patients with COVID-19; associations of hypertension, diabetes and presence of established cardiovascular disease (CVD) are larger, varying from 15 to 30% (average 21%), 5e20% (average 11%) and 2e40% (average 7%) respectively (Table 1) .

title:
  Comorbidities in COVID-19: Outcomes in hypertensive cohort and controversies with renin angiotensin system blockers

abstract:
  BACKGROUND AND AIMS: COVID-19 is already a pandemic. Emerging data suggest an increased association and a heightened mortality in patients of COVID-19 with comorbidities. We aimed to evaluate the outcome in hypertensive patients with COVID-19 and its relation to the use of renin-angiotensin system blockers (RASB). METHODS: We have systematically searched the medical database up to March 27, 2020 and retrieved all the published articles in English language related to our topic using MeSH key words. RESULTS: From the pooled data of all ten available Chinese studies (n = 2209) that have reported the characteristics of comorbidities in patients with COVID-19, hypertension was present in nearly 21%, followed by diabetes in nearly 11%, and established cardiovascular disease (CVD) in approximately 7% of patients. Although the emerging data hints to an increase in mortality in COVID-19 patients with known hypertension, diabetes and CVD, it should be noted that it was not adjusted for multiple confounding factors. Harm or benefit in COVID-19 patients receiving RASB has not been typically assessed in these studies yet, although mechanistically and plausibly both, benefit and harm is possible with these agents, given that COVID-19 expresses to tissues through the receptor of angiotensin converting enzyme-2. CONCLUSION: Special attention is definitely required in patients with COVID-19 with associated comorbidities including hypertension, diabetes and established CVD. Although the role of RASB has a mechanistic equipoise, patients with COVID-19 should not stop these drugs at this point of time, as recommended by various world organizations and without the advice of health care provider.


id: cord-342786-dl8vjwfn
title: COVID-19 Cardiovascular Epidemiology, Cellular Pathogenesis, Clinical Manifestations and Management
author: Sattar, Yasar
date: 2020-07-14
txt: ./txt/cord-342786-dl8vjwfn.txt
cache: ./cache/cord-342786-dl8vjwfn.txt
extension: .txt
mime: text/plain
url: https://api.elsevier.com/content/article/pii/S2352906720302876
doi: 10.1016/j.ijcha.2020.100589
summary:
  Abstract Coronavirus Disease 2019 (COVID-19) is a rapidly progressing global pandemic that may present with a variety of cardiac manifestations including, but not limited to, myocardial injury, myocardial infarction, arrhythmias, heart failure, cardiomyopathy, shock, thromboembolism, and cardiac arrest. Coronavirus Disease 2019 (COVID-19) is a rapidly progressing global pandemic that may present with a variety of cardiac manifestations including, but not limited to, myocardial injury, myocardial infarction, arrhythmias, heart failure, cardiomyopathy, shock, thromboembolism, and cardiac arrest. The infected patients may also present with cardiovascular disease (CVD) like acute coronary syndrome(ACS) and congestive cardiac failure(CHF) [6] . The systemic inflammation in COVID-19 may also dysregulate the post-translational modification of cardiac ion channels resulting in arrhythmia [25, 26] It is also noteworthy that viral proteins of SARS-CoV-2, ORF3 and ORF8, activate NLRP3 inflammasomes which inturn promotes atrial fibrillation [27, 28] .

abstract:
  Abstract Coronavirus Disease 2019 (COVID-19) is a rapidly progressing global pandemic that may present with a variety of cardiac manifestations including, but not limited to, myocardial injury, myocardial infarction, arrhythmias, heart failure, cardiomyopathy, shock, thromboembolism, and cardiac arrest. These cardiovascular effects are worse in patients who have pre-existing cardiac conditions such as coronary artery disease, hypertension, diabetes mellitus, and coagulation abnormalities. Other predisposing risk factors include advanced age, immunocompromised state, and underlying systemic inflammatory conditions. Here we review the cellular pathophysiology, clinical manifestations and treatment modalities of the cardiac manifestations seen in patients with COVID-19.


id: cord-346811-gorp9n1g
author: Hippisley-Cox, Julia
date: 2020-07-31
txt: ./txt/cord-346811-gorp9n1g.txt
cache: ./cache/cord-346811-gorp9n1g.txt
extension: .txt
mime: text/plain
url: https://doi.org/10.1136/heartjnl-2020-317393
doi: 10.1136/heartjnl-2020-317393
summary:
  We report a large, population-based study where we examined the drug histories of approximately 20% of all patients tested positive for coronavirus in England to determine if there was an independent association between ACE inhibitor and ARB drug prescription and severe COVID-19 disease susceptibility and progression. We extracted data from the GP record for explanatory and potential confounding variables including variables with some evidence of being risk factors for COVID-19 disease or severe disease as measured by ICU admission and variables likely to influence prescribing of ACE inhibitors and ARB medications. In this very large population-based study, ACE inhibitor and ARB prescriptions were associated with a reduced risk of COVID-19 RT-PCR positive disease, having adjusted for a wide range of demographic factors, potential comorbidities and other medication. 11 In our study, prior prescription of ACE inhibitor and ARB drugs did not have a significant effect on the risk of patients developing COVID-19 disease severe enough to require ICU care.

title:
  Risk of severe COVID-19 disease with ACE inhibitors and angiotensin receptor blockers: cohort study including 8.3 million people

abstract:
  BACKGROUND: There is uncertainty about the associations of angiotensive enzyme (ACE) inhibitor and angiotensin receptor blocker (ARB) drugs with COVID-19 disease. We studied whether patients prescribed these drugs had altered risks of contracting severe COVID-19 disease and receiving associated intensive care unit (ICU) admission. METHODS: This was a prospective cohort study using routinely collected data from 1205 general practices in England with 8.28 million participants aged 20–99 years. We used Cox proportional hazards models to derive adjusted HRs for exposure to ACE inhibitor and ARB drugs adjusted for sociodemographic factors, concurrent medications and geographical region. The primary outcomes were: (a) COVID-19 RT-PCR diagnosed disease and (b) COVID-19 disease resulting in ICU care. FINDINGS: Of 19 486 patients who had COVID-19 disease, 1286 received ICU care. ACE inhibitors were associated with a significantly reduced risk of COVID-19 disease (adjusted HR 0.71, 95% CI 0.67 to 0.74) but no increased risk of ICU care (adjusted HR 0.89, 95% CI 0.75 to 1.06) after adjusting for a wide range of confounders. Adjusted HRs for ARBs were 0.63 (95% CI 0.59 to 0.67) for COVID-19 disease and 1.02 (95% CI 0.83 to 1.25) for ICU care. There were significant interactions between ethnicity and ACE inhibitors and ARBs for COVID-19 disease. The risk of COVID-19 disease associated with ACE inhibitors was higher in Caribbean (adjusted HR 1.05, 95% CI 0.87 to 1.28) and Black African (adjusted HR 1.31, 95% CI 1.08 to 1.59) groups than the white group (adjusted HR 0.66, 95% CI 0.63 to 0.70). A higher risk of COVID-19 with ARBs was seen for Black African (adjusted HR 1.24, 95% CI 0.99 to 1.58) than the white (adjusted HR 0.56, 95% CI 0.52 to 0.62) group. INTERPRETATION: ACE inhibitors and ARBs are associated with reduced risks of COVID-19 disease after adjusting for a wide range of variables. Neither ACE inhibitors nor ARBs are associated with significantly increased risks of receiving ICU care. Variations between different ethnic groups raise the possibility of ethnic-specific effects of ACE inhibitors/ARBs on COVID-19 disease susceptibility and severity which deserves further study.


id: cord-346912-o09qmp7x
title: A Macroeconomic SIR Model for COVID-19
author: Bayraktar, E.
date: 2020-06-23
txt: ./txt/cord-346912-o09qmp7x.txt
cache: ./cache/cord-346912-o09qmp7x.txt
extension: .txt
mime: text/plain
url: http://medrxiv.org/cgi/content/short/2020.06.22.20137711v1?rss=1
doi: 10.1101/2020.06.22.20137711
summary:
  We develop an SIR model of the COVID-19 pandemic which explicitly considers herd immunity, behavior-dependent transmission rates, remote workers, and indirect externalities of lockdown. Additionally, if we incorporate a behavior-dependent transmission rate which represents increased personal caution in response to increased infection levels, both output loss and total mortality are lowered. Overall, our model predicts that a lockdown which ends at the arrival of herd immunity, combined with individual actions to slow virus transmission, can reduce total mortality to one-third of the no-lockdown level, while allowing high-risk individuals to leave lockdown well before vaccine arrival. • Increasing the level of remote work reduces the impact of COVID-19 by decreasing both mortality and output loss, even though a longer lockdown is imposed. Recreation of [Ace+20] model (two groups and no herd immunity), parameters from Table 1 Output Loss: 8.9676%, Total Deaths: 1.3121% All rights reserved.

abstract:
  The current COVID-19 pandemic and subsequent lockdowns have highlighted the close and delicate relationship between a country's public health and economic health. Macroeconomic models which use preexisting epidemic models to calculate the impacts of a disease outbreak are therefore extremely useful for policymakers seeking to evaluate the best course of action in such a crisis. We develop an SIR model of the COVID-19 pandemic which explicitly considers herd immunity, behavior-dependent transmission rates, remote workers, and indirect externalities of lockdown. This model is presented as an exit time control problem where the lockdown ends when the population achieves herd immunity, either naturally or via a vaccine. A social planner prescribes separate levels of lockdown for two separate sections of the adult population - those who are low-risk (ages 20-64) and those who are high-risk (ages 65 and over). These levels are determined via optimization of an objective function which assigns a macroeconomic cost to the level of lockdown and the number of deaths. We find that, by ending lockdowns once herd immunity is reached, high-risk individuals are able to leave lockdown significantly before the arrival of a vaccine without causing large increases in mortality. Additionally, if we incorporate a behavior-dependent transmission rate which represents increased personal caution in response to increased infection levels, both output loss and total mortality are lowered. Lockdown efficacy is further increased when there is less interaction between low- and high-risk individuals, and increased remote work decreases output losses. Overall, our model predicts that a lockdown which ends at the arrival of herd immunity, combined with individual actions to slow virus transmission, can reduce total mortality to one-third of the no-lockdown level, while allowing high-risk individuals to leave lockdown well before vaccine arrival.


id: cord-349445-yh6ndtgm
title: Targeting Neprilysin (NEP) pathways: A potential new hope to defeat COVID-19 ghost
author: Mohammed El Tabaa, Manar
date: 2020-05-27
txt: ./txt/cord-349445-yh6ndtgm.txt
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url: https://api.elsevier.com/content/article/pii/S0006295220302914
doi: 10.1016/j.bcp.2020.114057
summary:
  Therefore, researchers suggested that the use of angiotensin converting enzyme inhibitors (ACEIs) and/or angiotensin receptor blockers (ARBs), may show a positive trend towards the severe inflammatory reactions and endothelial dysfunction caused by stimulating the function of ACE/Ang II/AT-1 axis and thereby, towards the bad pulmonary effects associated with the COVID-19 infection [29, 30] . Since IL-6 would inactivate endothelial nitric oxide synthase (eNOS), it could disrupt NO production [90] , decreasing its level and inducing a state of oxidative stress that may lead to Ang II-induced impairment in endothelial responses [91] Postulating impaired endothelium functions as a principal factor in the pathogenesis of heart failure, hypertension and diabetes, it will be expected to classify the patients of such diseases as high risk groups for COVID-19 development [92] [93] [94] . Taken into consideration the numerous harmful effects possibly induced by Ang II during COVID-19 pathogenesis, we found that most novel studies aim to use the anti-hypertensive drugs which act either by inhibiting the ACE activity or by blocking AT1 receptor, suggesting that action may mitigate the disease severity in COVID-19 patients.

abstract:
  COVID-19 is an ongoing viral pandemic disease that is caused by SARS-CoV2, inducing severe pneumonia in humans. However, several classes of repurposed drugs have been recommended, no specific vaccines or effective therapeutic interventions for COVID-19 are developed till now. Viral dependence on ACE-2, as entry receptors, drove the researchers into RAS impact on COVID-19 pathogenesis. Several evidences have pointed at Neprilysin (NEP) as one of pulmonary RAS components. Considering the protective effect of NEP against pulmonary inflammatory reactions and fibrosis, it is suggested to direct the future efforts towards its potential role in COVID-19 pathophysiology. Thus, the review aimed to shed light on the potential beneficial effects of NEP pathways as a novel target for COVID-19 therapy by summarizing its possible molecular mechanisms. Additional experimental and clinical studies explaining more the relationships between NEP and COVID-19 will greatly benefit in designing the future treatment approaches.


id: cord-351567-ifoe8x28
title: SARS-CoV-2 and Coronavirus Disease 2019: What We Know So Far
author: Rabi, Firas A.
date: 2020-03-20
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url: https://doi.org/10.3390/pathogens9030231
doi: 10.3390/pathogens9030231
summary:
  However, by that time, travelers had carried the virus to many countries, sparking memories of the previous coronavirus epidemics, severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS), and causing widespread media attention and panic. To assess the magnitude of the risk posed by the SARS-CoV-2, we review four parameters that we believe important: the transmission rate, the incubation period, the case fatality rate (CFR), and the determination of whether asymptomatic transmission can occur. A small study of 17 patients showed that nasal viral load peaks within days of symptom onset, suggesting that transmission of disease is more likely to occur early in the course of infection [40] . Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: A descriptive study The Epidemiological Characteristics of an Outbreak of 2019 Novel Coronavirus Diseases (COVID-19)-China 2020 Early Transmission Dynamics in Wuhan, China, of Novel Coronavirus-Infected Pneumonia

abstract:
  In December 2019, a cluster of fatal pneumonia cases presented in Wuhan, China. They were caused by a previously unknown coronavirus. All patients had been associated with the Wuhan Wholefood market, where seafood and live animals are sold. The virus spread rapidly and public health authorities in China initiated a containment effort. However, by that time, travelers had carried the virus to many countries, sparking memories of the previous coronavirus epidemics, severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS), and causing widespread media attention and panic. Based on clinical criteria and available serological and molecular information, the new disease was called coronavirus disease of 2019 (COVID-19), and the novel coronavirus was called SARS Coronavirus-2 (SARS-CoV-2), emphasizing its close relationship to the 2002 SARS virus (SARS-CoV). The scientific community raced to uncover the origin of the virus, understand the pathogenesis of the disease, develop treatment options, define the risk factors, and work on vaccine development. Here we present a summary of current knowledge regarding the novel coronavirus and the disease it causes.


id: cord-352230-8mazd3eu
title: Strategies for Targeting SARS CoV-2: Small Molecule Inhibitors—The Current Status
author: Beeraka, Narasimha M.
date: 2020-09-18
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url: https://doi.org/10.3389/fimmu.2020.552925
doi: 10.3389/fimmu.2020.552925
summary:
  Severe Acute Respiratory Syndrome-Corona Virus-2 (SARS-CoV-2) induced Coronavirus Disease 19 (COVID-19) cases have been increasing at an alarming rate (7.4 million positive cases as on June 11 2020), causing high mortality (4,17,956 deaths as on June 11 2020) and economic loss (a 3.2% shrink in global economy in 2020) across 212 countries globally. SARS-CoV-2 infection is mediated by the binding of viral Spike proteins (S-protein) to human cells through a 2-step process, which involves Angiotensin Converting Enzyme-2 (ACE2) and Transmembrane Serine Protease (TMPRSS)-2. Therefore, in this review, we have reviewed structural features of SARS-CoV-2 with special emphasis on key molecular targets and their known modulators that can be considered for the development of NSMIs. COVID-19 is a devastating disease caused by a coronavirus related to the one that caused outbreaks of Severe Acute Respiratory Syndrome (SARS) in the year 2002 (1, 2) .

abstract:
  Severe Acute Respiratory Syndrome-Corona Virus-2 (SARS-CoV-2) induced Coronavirus Disease - 19 (COVID-19) cases have been increasing at an alarming rate (7.4 million positive cases as on June 11 2020), causing high mortality (4,17,956 deaths as on June 11 2020) and economic loss (a 3.2% shrink in global economy in 2020) across 212 countries globally. The clinical manifestations of this disease are pneumonia, lung injury, inflammation, and severe acute respiratory syndrome (SARS). Currently, there is no vaccine or effective pharmacological agents available for the prevention/treatment of SARS-CoV2 infections. Moreover, development of a suitable vaccine is a challenging task due to antibody-dependent enhancement (ADE) and Th-2 immunopathology, which aggravates infection with SARS-CoV-2. Furthermore, the emerging SARS-CoV-2 strain exhibits several distinct genomic and structural patterns compared to other coronavirus strains, making the development of a suitable vaccine even more difficult. Therefore, the identification of novel small molecule inhibitors (NSMIs) that can interfere with viral entry or viral propagation is of special interest and is vital in managing already infected cases. SARS-CoV-2 infection is mediated by the binding of viral Spike proteins (S-protein) to human cells through a 2-step process, which involves Angiotensin Converting Enzyme-2 (ACE2) and Transmembrane Serine Protease (TMPRSS)-2. Therefore, the development of novel inhibitors of ACE2/TMPRSS2 is likely to be beneficial in combating SARS-CoV-2 infections. However, the usage of ACE-2 inhibitors to block the SARS-CoV-2 viral entry requires additional studies as there are conflicting findings and severe health complications reported for these inhibitors in patients. Hence, the current interest is shifted toward the development of NSMIs, which includes natural antiviral phytochemicals and Nrf-2 activators to manage a SARS-CoV-2 infection. It is imperative to investigate the efficacy of existing antiviral phytochemicals and Nrf-2 activators to mitigate the SARS-CoV-2-mediated oxidative stress. Therefore, in this review, we have reviewed structural features of SARS-CoV-2 with special emphasis on key molecular targets and their known modulators that can be considered for the development of NSMIs.


id: cord-353707-3n2nji8l
author: Sunden-Cullberg, Jonas
date: 2020-04-28
txt: ./txt/cord-353707-3n2nji8l.txt
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url: https://doi.org/10.1161/hypertensionaha.120.15178
doi: 10.1161/hypertensionaha.120.15178
abstract: nan
summary:
  title: Chronic Use of Angiotensin-Converting Enzyme Inhibitors and Angiotensin II Receptor Blockers Is High Among Intensive Care Unit Patients With Non–COVID-19 Sepsis but Carries a Moderately Increased Risk of Death We, therefore, examined the chronic use of ACE inhibitors/ARBs and associated mortality in a historic cohort of septic patients admitted to the Intensive Care Unit. Data were collected between January 2008 and December 2015 on a nationwide Swedish cohort of 2700 patients, aged 18 years and over, with community-acquired severe sepsis and septic shock admitted to the Intensive Care Unit within 24 hours of arrival to any of 32 emergency departments throughout the country. ACE inhibitors/ ARB use was common among patients admitted to the Intensive Care Unit because of sepsis. ACE inhibitors/ARB use and associated mortality among critically ill COVID-19 patients can be compared with this data. Hypothesis: angiotensin-converting enzyme inhibitors and angiotensin receptor blockers may increase the risk of severe COVID-19

title:
  Chronic Use of Angiotensin-Converting Enzyme Inhibitors and Angiotensin II Receptor Blockers Is High Among Intensive Care Unit Patients With Non–COVID-19 Sepsis but Carries a Moderately Increased Risk of Death


id: cord-355807-q3bngari
author: Yepes-Pérez, Andres F.
date: 2020-10-29
txt: ./txt/cord-355807-q3bngari.txt
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url: https://doi.org/10.1080/07391102.2020.1837676
doi: 10.1080/07391102.2020.1837676
summary:
  Molecular modeling was carried out to evaluate the potential antiviral properties of the components of the medicinal herb Uncaria tomentosa (cat''s claw) focusing on the binding interface of the RBD–ACE-2 and the viral spike protein. tomentosa against focusing both on the binding interface of the RBD-ACE-2 and inside SARS-CoV-2 RBD spike protein, (2) simulations of ligand pathway of the best predicted compounds from step 1 to evaluate convenient entrance mechanism of the compounds to the binding site, (3) MD simulation to assess the stability of the best protein-ligand complexes from 1, (4) calculation of pharmacokinetics parameters for the most qualified compounds resulting from the previous parts of the docking protocol. Next, we used the cryo-EM structure of SARS-CoV-2 spike protein (PDB code: 6VYB) in their open state (Lipinski et al., 2012) to explore the potential inhibition of components of the cat''s claw, selecting ACE-2-binding pocket to this study.

title:
  Uncaria tomentosa (cat’s claw): a promising herbal medicine against SARS-CoV-2/ACE-2 junction and SARS-CoV-2 spike protein based on molecular modeling

abstract:
  COVID-19 is a novel severe acute respiratory syndrome coronavirus. Currently, there is no effective treatment and vaccines seem to be the solution in the future. Virtual screening of potential drugs against the S protein of severe acute respiratory syndrome corona virus 2 (SARS-CoV-2) has provided small molecular compounds with a high binding affinity. Unfortunately, most of these drugs do not attach with the binding interface of the receptor-binding domain (RBD)–angiotensin-converting enzyme-2 (ACE-2) complex in host cells. Molecular modeling was carried out to evaluate the potential antiviral properties of the components of the medicinal herb Uncaria tomentosa (cat’s claw) focusing on the binding interface of the RBD–ACE-2 and the viral spike protein. The in silico approach starts with protein–ligand docking of 26 Cat’s claw key components followed by molecular dynamics simulations and re-docked calculations. Finally, we carried out drug-likeness calculations for the most qualified cat’s claw components. The structural bioinformatics approaches led to the identification of several bioactive compounds of U. tomentosa with potential therapeutic effect by dual strong interaction with interface of the RBD–ACE-2 and the ACE-2 binding site on SARS-CoV-2 RBD viral spike. In addition, in silico drug-likeness indices for these components were calculated and showed good predicted therapeutic profiles of these phytochemicals found in U. tomentosa (cat’s claw). Our findings suggest the potential effectiveness of cat’s claw as complementary and/or alternative medicine for COVID-19 treatment. Communicated by Ramaswamy H. Sarma


