key: cord-0745764-rd8gpo10 authors: Ghafouri-Fard, Soudeh; Noroozi, Rezvan; Omrani, Mir Davood; Branicki, Wojciech; Pośpiech, Ewelina; Sayad, Arezou; Pyrc, Krzysztof; Łabaj, Paweł P.; Vafaee, Reza; Taheri, Mohammad; Sanak, Marek title: Angiotensin converting enzyme: A review on expression profile and its association with human disorders with special focus on SARS-CoV-2 infection date: 2020-05-11 journal: Vascul Pharmacol DOI: 10.1016/j.vph.2020.106680 sha: 3a6f155a213f44260bbfed4355d5e67f5f40ec1d doc_id: 745764 cord_uid: rd8gpo10 Angiotensin-converting enzyme (ACE) and its homologue, ACE2, have been mostly associated with hypertensive disorder. However, recent pandemia of SARS-CoV-2 has put these proteins at the center of attention, as this virus has been shown to exploit ACE2 protein to enter cells. Clear difference in the response of affected patients to this virus has urged researchers to find the molecular basis and pathophysiology of the cell response to this virus. Different levels of expression and function of ACE proteins, underlying disorders, consumption of certain medications and the existence of certain genomic variants within ACE genes are possible explanations for the observed difference in the response of individuals to the SARS-CoV-2 infection. In the current review, we discuss the putative mechanisms for this observation. Angiotensin-converting enzyme (ACE) has its homologue, ACE2 discovered in 2000 as a ACE related caroxypeptidase not inhibited by captopril (1, 2) . ACE2 was firstly shown to be expressed in the kidneys of both the normotensive and the spontaneously hypertensive rat strains (3) . Subsequent studies demonstrated down-regulation of renal ACE2 in three different models of hypertension (4) . Moreover, circulating and cardiac levels of angiotensin II (AT-II) were shown to increase in the ACE2-null mice. ACE2 is the principal pathway for Ang-(1-7) formation from AT-II (Ang-1-8), protecting against excessive activation of AT1 receptor in the heart tissues, However, newer findings suggested that ACE2 can be an important element in the renin-angiotensin aldosterone system (5) . Following these studies, ACE and ACE2 focused the attention of researchers for their contribution in diverse human disorders. Recently, the new coronavirus (2019-nCoV or SARS-CoV-2) outbreak which has affected people all over the world has further highlighted the role of ACE2. This virus has about 80% sequence identity with the severe acute respiratory syndrome (SARS)-related coronaviruses (SARS-CoVs) and 96% sequence identity to a bat coronavirus. Most remarkably, SARS-COV-2 was shown to utilize the similar cell entry receptor ACE2 as SARS-CoV (6, 7). A recent study has shown that the ACE2-binding pocket for SARS-CoV-2 spike protein receptor-binding domain (RBD) is almost identical to this one of SARS-CoV RBD. Structural protein modeling led to identification of amino acid residues in SARS-CoV-2 RBD that critical in ACE2 binding. Notably, most of these residues are either highly conserved or have comparable side chain chemical properties with the SARS-CoV RBD. This similarity of the structure and amino acid sequence stimulated intensive debate on the convergent evolution of these viruses RBDs under a pressure of enhanced binding to ACE2 (8) . ACE2 has been shown to be expressed as a membrane bound protein in several human tissues such as lung, intestine, heart and kidney. The surface expression of this protein on was J o u r n a l P r e -p r o o f demonstrated on ciliated bronchial cells and on the lung alveolar epithelial cells but also in endothelial cells, which was stated a noticeable discovery (9) . Moreover, a recent in silico analysis of RNA-seq profiles verified expression of ACE2 in the mucosa of oral cavity (10) . Figure 1 shows the molecular mechanisms initiated after SARS-CoVs entry into the cells and the significance of ACE and ACE2 in these processes. Then, ACE converts AT-I to AT-II. Finally, ACE2 cleaves AT-II to produce AT-(1-7). AT-II can bind with AT1R to initiate inflammation and fibrosis in lung tissue. However, binding of AT-(1-7) with MasR inhibits this process. SARS-CoVs exploits ACE2 for their entrance into the cells. A transmembrane serine protease TMPRSS2 has a crucial role in activation of the fusion of a virus with cell membrane. Moreover, the Furin protease which is proconvertase physiologically required to activate proteins in the Golgi apparatus mediates proteolysis of the spike protein S2 subunit, an unique feature for SARS-CoV-2 (11) . ACE2 levels are decreased in SARS-CoV infected cells leading to increase in AT-II and decrease in AT- (1) (2) (3) (4) (5) (6) (7) J o u r n a l P r e -p r o o f levels. Based on receptor effects of these proteins mediated by AT1R and MasR, these two alterations have synergic effects on induction of lung fibrosis. Moreover, AT-II has a role in degradation of ACE2 through ubiquitination (12) . SARS-CoVs also enhance expression levels of miR-200c-3p and miR-429 in the infected cells, both of them being regarded as ACE2 targeting miRNAs (13, 14) (ACE: angiotensin converting enzyme, ACEi: ACE inhibitor, AT: angiotensinogen, ARB: Angiotensin II receptor blocker). In the current review, we discuss the expression pattern and function of the both ACE proteins in relation with the underlying disorders, administration of certain medications and the existence of common genomic variants within ACE genes to explain the differences in the response of affected individuals to SARS-COV-2. In agreement with the role of ACE2 on virus uptake by cells, up-regulation of human ACE2 has increased disease severity in mice infected with SARS-CoV (15) . Moreover, injecting SARS-CoV spike into mice has led to down-regulation of ACE2, thus aggravating the lung injury (16, 17) . Consequently, ACE2 functions as the cellular receptor for SARS-CoV entrance but also confers a protective mechanism against lung injury (18) . Based on these investigations, level of expression of ACE2 is an important factor in the SARS-CoV infection. Thus, comorbid conditions that influence expression of this protein might affect severity of disease. Table 1 summarizes the available data on abnormal expression of ACE and ACE2 in human/ animal disorders. Several medications have been shown to alter expression levels of ACE or ACE2. Administration of these medications not only can modify a risk of infection with SARS-CoV, but also can affect the disease course. Table 2 summarizes the results of studies which reported alteration of ACE or ACE2 levels following administration of certain medications. J o u r n a l P r e -p r o o f Several potentially functional gene polymorphisms have been identified in ACE and ACE2. Table 3 shows the results studies which assessed the association between ACE polymorphisms and human disorders. MicoRNA (miRNAs) as regulators of gene expression have been involved in several ACErelated pathways and have been shown to alter expression of ACE proteins or being altered by ACE proteins. These small-sized RNAs can bind with the 3′ untranslated region (3′ UTR) of their targets to stimulate degradation of the target mRNA and suppress translation. Moreover, miRNAs can interact with 5′ UTR, coding regions, and promoters, thus regulating gene expression by various mechanisms. Secretion of miRNAs in extracellular components provides them the ability to participate in the cell-cell communication (85) . Table 4 shows the results of studies which assessed association between miRNAs and ACE proteins. On the other hand, a meta-analysis has reported association between the administration of ACE inhibitors and reduction in risk of pneumonia. Notably, ACE inhibitors may be more efficient in reducing the risk of pneumonia in Asian patients. Also, treatment with ACE J o u r n a l P r e -p r o o f inhibitors was associated with a significant reduction in risk of pneumonia-related mortality compared with controls (96) . This may be also related to the dual effect of ACE2 in viral infection and protection against acute respiratory distress syndrome. Although the ACE/ACE2 regulation is complicated, it seems that in the absence of ACE the accumulation of angiotensin I may lead to the upregulation of ACE2. Whether this could facilitate the viral infection, is plausible because ACE2 is considered as a specific target for coronavirus treatment (95) . It means that the population-based differences in the ACE2 expression may affect the efficacy of a future antiviral treatment. In brief, we summarize that coronaviruses, such as SARS-CoV and SARS-CoV-2, utilize ACE2 receptor for cell entry and infection. We know that the most severe consequence of the expression. In addition to the routine models for investigation of the pathological events during infections, tissue engineering methods particularly "advanced biomaterials" or "functionalized scaffolds" (101) would provide study models to investigate the potential of such approaches in the treatment of the disorder. As an advance in the field of functional studies, the obtained results from "safe" in-vitro models which work without any additive can be applied in human models (102) . 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A first step in understanding SARS pathogenesis High expression of ACE2 receptor of 2019-nCoV on the epithelial cells of oral mucosa TMPRSS2 and ADAM17 cleave ACE2 differentially and only proteolysis by TMPRSS2 augments entry driven by the severe acute respiratory syndrome coronavirus spike protein Angiotensin Converting Enzyme 2: A Double-Edged Sword miRNA-200c-3p is crucial in acute respiratory distress syndrome. 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The Lancet Increasing Host Cellular Receptor-Angiotensin-Converting Enzyme 2 (ACE2) Expression by Coronavirus may Facilitate 2019-nCoV Infection ACE2and TMPRSS2 variants and expression as candidates to sex and country differences in COVID-19 severity in Italy Individual Variation of the SARS-CoV2 Receptor ACE2 Gene Expression and Regulation Advances in Nanotechnology for the Treatment of Osteoporosis Highly efficient in vitro reparative behaviour of dental pulp stem cells cultured with standardised platelet lysate supplementation The first step of conversion of angiotensinogen (AT) to AT-I is catalyzed by renin. Then, ACE converts AT-I to AT-II. Finally, ACE2 cleaves AT-II to produce AT-(1-7). AT-II can bind with AT1R to initiate inflammation and fibrosis in lung tissue. However, binding of AT-(1-7) with MasR inhibits this process. SARS-CoVs exploits ACE2 for their entrance into the cells. A transmembrane serine protease TMPRSS2 has a crucial role in activation of the fusion of a virus with cell membrane. Moreover, the Furin protease which is proconvertase physiologically required to activate proteins in the Golgi apparatus mediates proteolysis of the spike protein S2 subunit, an unique feature for SARS-CoV-2.