key: cord-0803815-pe0lpi5d
authors: Bosso, Mira; Thanaraj, Thangavel Alphonse; Abu-Farha, Mohamed; Alanbaei, Muath; Abubaker, Jehad; Al-Mulla, Fahd
title: The two faces of ACE2: The Role of ACE2 receptor and its polymorphisms in hypertension and COVID-19
date: 2020-06-25
journal: Mol Ther Methods Clin Dev
DOI: 10.1016/j.omtm.2020.06.017
sha: e69fd924945a533f6756779cff902c5516608b9a
doc_id: 803815
cord_uid: pe0lpi5d

Abstract The mechanism for the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection requires the binding of the virus to the angiotensin-converting enzyme 2 (ACE2) receptor, well-known for its role in counteracting ACE. ACE2 is involved in modulating blood pressure and establishing blood pressure homeostasis. Recently, a critical debatable question has risen, whether using antihypertensive medications will have a favorable impact on people infected with SARS-CoV-2 or a deleterious one, mainly since ACEIs and ARBs therapy can modulate the expression of ACE2 protein. The concern is that the use of ACEIs and ARBs will increase the expression of ACE2 and increase patient susceptibility to viral host cell entry and propagation. On the other hand, several genetic association studies have examined the relationship between ACE2 genetic variants and the risk of developing hypertension in different ethnic populations. In this review, we discuss the ongoing arguments in the literature about ACE2’s role in mortality rate among COVID-19 people comorbid with hypertension and critically evaluate the current debate about the usage or discontinuation of ACEI/ARB antihypertensive drugs. Moreover, we explore the two opposing roles that ACE2 genetic variants might be playing in COVID-19 disease by reducing ACE2 receptor effectiveness and mitigating SARS-CoV-2 infectivity.

Coronavirus disease 2019 (COVID-19) is an ongoing pandemic of acute respiratory 59 disease caused by the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). The 60 mortality rates as well as the infectious capacity of the virus, ranging from 1% to >5%, has 61 raised a major concern worldwide. Older people with comorbid conditions such as pulmonary 62 disease, cardiac disease, kidney disease, diabetes, and hypertension are associated with higher 63 mortality rates. 1 According to recent literature reports, it is now well accepted that 64 hypertension is associated with increased mortality rates in COVID-19 patients. The mechanism for SARS-CoV-2 infection necessitates the binding of the virus to the 70 membrane-bound form of angiotensin-converting enzyme 2 (ACE2) receptor and internalization 71 of the complex by the host cell (Figure 1) . Apart from its role as a receptor for SARS-CoV-2 (and 72 for both the SARS-CoV and the related human respiratory coronavirus NL63), ACE2 is well-73 known for its role in hypertension. ACE2 modulates blood pressure and maintains blood 74 pressure homeostasis through negatively regulating the Renin-Angiotensin System (RAS). 4,5 75

Angiotensin-converting enzyme (ACE) and its homolog ACE2 are two key enzymes involved in 76 the synthesis of bioactive components of the RAS. 6 ACE2 exerts its functions through cleaving 77 either Angiotensin I or Angiotensin II into the inactive peptides Angiotensin (1-9) and 78

Angiotensin (1-7) respectively (Figure 1) . Angiotensin (1-9) gets further metabolized into 79

Angiotensin (1-7). Angiotensin (1-7) is a vasodilator, hence, ACE2 counteracts the 80 vasoconstrictor effects of the ACE-Angiotensin II axis. The mechanism by which ACE2 81 antagonizes the effects of Angiotensin II is either by cleaving the precursor Angiotensin I which 82 reduces Ang II synthesis in tissues or by directly hydrolyzing Angiotensin II and reducing its 83 levels in plasma. 84

Both ACE and ACE2 are endothelium-bound carboxypeptidases that can be cleaved by 85 different metalloproteases located on the cell surface and released in a soluble form. Contrary 86 to ACE which is widely expressed in many tissues and organs, ACE2's high expression is confined 87 to the endothelial cells of the arteries, arterioles, and venules of the heart and Kidney. 4 88 Therefore, ACE2 has been a potential therapeutic target in treating hypertension as well as 89 cardiac dysfunctions. Several animal studies, carried out on diet-induced hypertension rat 90 models, have established a link between increased blood pressure and reduced mRNA 91 expression and protein levels of ACE2. Data showed that low levels of ACE2 can lead to elevated 92 levels of Ang II and consequently hypertension. 4 Animal studies have suggested that 93 angiotensin-converting-enzyme (ACE) inhibitors and angiotensin-receptor blockers (ARBs) may 94 upregulate ACE2 expression, thus increasing the availability of target molecules for SARS-CoV-2. 95

The Leeds Family Study by Rice et al (2006) , is one of the first studies to demonstrate 96 the link of ACE2 polymorphisms and inheritance of hypertension, and levels of circulating 97 ACE2. 7 Several genetic association studies have examined the relationship between ACE2 98 genetic variants and the risk of developing hypertension in different ethnic populations (Table  99 1). 8 One of the highly reported variants is rs2285666; AG genotype at this variant is protective 100 as it poses a lower risk to develop hypertension in females. 9,10 In contrast, AA genotype as 101 opposed to AG+GG at the same SNP rs2285666 has been reported to be associated with a 102 higher risk of hypertension in different ethnic populations. 11-13 Other highly reported variants 103 known to be associated with high risk to develop hypertension are rs2106809 with TT genotype 104 and rs879922 with C allele. 10,14-18 However, the European population study revealed the 105 absence of an association between rs879922 and high blood pressure. 19 there are concerns on whether medical management of hypertension involving the use of 112 inhibitors of the renin-angiotensin-aldosterone system (RAAS) (such as ACEIs and ARBs) have a 113 favorable impact on people infected with SARS-CoV-2 or a deleterious one mainly because ACEI 114 and ARB therapies can modulate the expression of ACE2. The concern is that the use of ACEIs 115 and ARBs will increase the expression of ACE2 and increase patient susceptibility to viral host 116 cell entry and propagation. As a result, there has been a call for the discontinuation of 117 ACEI/ARB usage prophylactically and in the context of suspected COVID-19 cases. 118

In this review, we shed light on the current debate about ACE2 role in the mortality 119 associated with COVID-19 cases with hypertension and weigh on the current argument about 120 the usage or discontinuation of ACEI/ARB hypertensive medication. Finally, we explore the role 121 of ACE2 genetic variants in the predisposition for hypertension and the response to However, a critical question that remains unanswered is whether this 129 association is solely attributed to the pathogenesis of hypertension or to the associated 130 comorbidity or therapy. In this section, we review recent findings regarding the role of 131 antihypertensive medications, which have been at the center of a considerable debate, namely 132 angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs). The 133 main question has been whether they have a favorable impact on the people infected with 134 SARS-CoV-2 or a deleterious one mainly since ACEI and ARB therapies can modulate the 135 expression of angiotensin-converting enzyme 2 (ACE2), that has been identified as a receptor 136

for SARS-COV2. The concern is that the use of ACEIs and ARBs will increase the expression of 137 ACE2 and increase patient susceptibility to viral host cell entry and propagation. As a result, 138 there has been a call for the discontinuation of ACEIs/ARBs usage prophylactically and in the 139

On the other hand, other groups have been suggesting the opposite where increased 141 ACE2 can act as a vasodilator, antioxidant, and anti-inflammatory. This is since ACE2 primarily 142 acts to counterpoise the effect of ACE. As ACE produces angiotensin II from angiotensin I, ACE2 143 generates angiotensin (1-9) from Angiotensin I or angiotensin (1-7) from Angiotensin II that none of these medications (ACEIs, ARBs, beta-blockers, calcium-channel blockers, or 168 thiazide diuretics) was associated with increased infectivity to SARS-CoV-2 or increased COVID-169 19 severity. The study predefined a 10% difference as a substantial difference, even though the 170 study was powered to detect as low as a 6% difference. It is worth mentioning that the data 171 pointed to a modest decrease in the likelihood of testing positive for SARS-CoV-2 but not the 172 severity in patients taking beta-blockers that was slightly significant in an analysis that included insurance, or health care access in propensity scores. 23 Nonetheless, both the studies 176 highlighted that ACEIs and ARBs, as well as other antihypertensive drugs were safe to use. 23 Their data showed that treatment with ACE-inhibitors was associated with a reduced risk of 188 rapidly deteriorating severe disease. There was a lesser rate of death or transfer to the ICU 189 within 7 days in patients on an ACE-inhibitor; an odds ratio of 0.29 (CI 0.10-0.75; p<0.01) was 190 observed after adjusting for age, gender, several comorbidities such as hypertension, diabetes 191 mellitus, ischemic heart disease, and heart failure. They concluded that among hospitalized Table 2) . 215

While two of the variants, namely rs112171234 and rs75979613 downregulate the expression 216 of ACE2, the others upregulate. The eQTL variants are from the following genes: the intergenic 217 region of (ACE2, BMX), FANCB, the intergenic region of (MOSPD2, ASB9), ACE2, the intergenic 218 region of (CA5BP1, CA5B) and CLTRN. Almost all these variants are "common" variants (minor 219 allele frequency ≥ 5%) in one or the other population raising the possibility that genetic 220 regulation of ACE2 expression can be more widespread. However, none of these variants is 221 associated with hypertension in any of the global studies ruling out the possibility of a common 222 genetic mechanism for the onset of hypertension and SARS-CoV-2 infection. Even at the level of 223 genes, which harbor these eQTL variants, none other than ACE2 is known to be directly 224 involved in the onset of hypertension and the COVID-19; however, it requires further studies to 225 examine whether these genes are contributing to more extensive pathways regulating 226 hypertension or COVID-19 disease. 227 In several trials, COVID-19 patients who already were taking these drugs are being 308 randomized to continue or to stop them. Furthermore, we must consider the higher rate of 309 cardiac injury and adverse outcomes in hypertensive patients during the COVID-19 pandemic. 310

Undeniably, the loss of ACEIs/ARBs cardiopulmonary protective effects could be damaging. 311

Additionally, based on genetic analysis, the eQTL variants regulating the expression of ACE2 312 gene are not so far shown to be associated with hypertension; however, the ACE2 313 polymorphisms associated with hypertension or with the efficacy of ACEI or ARB could have the 314 potential to alter the binding of SARS-COV-2 spike protein with ACE2 receptor. Moreover, it 315 requires further studies involving large cohorts to evaluate the genetic association of the 316 above-mentioned eQTL variants and the gene loci with hypertension traits and to evaluate the 317 involvement of the above-mentioned gene loci that affect the efficacy of ACEI and ARB in SARS-318

CoV-2 infection and proliferation. Hence, ACEIs/ARBs chronic therapy should not be 319 discontinued in hypertensive patients with COVID-19. Moreover, in the absence of adequate 320 follow-up visits, changing ACEIs/ARBs with another anti-hypertensive therapy could lead to 321 inadequate control of blood pressure. Thus, as recommended by several medical associations, 322 and in light of more scientific evidence supporting their beneficial/non-harmful impact, 323

ACEIs/ARBs should be continued in COVID-19 patients. 

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