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The Two Faces of ACE2: The Role of ACE2 Receptor and Its Polymorphisms in Hypertension and COVID-19

2020; Cell Press; Volume: 18; Linguagem: Inglês

10.1016/j.omtm.2020.06.017

2329-0501

Mira Bosso, Thangavel Alphonse Thanaraj, Mohamed Abu‐Farha, Muath Alanbaei, Jehad Abubaker, Fahd Al‐Mulla,

Renin-Angiotensin System Studies

The mechanism for 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 arisen whether using antihypertensive medications will have a favorable impact on people infected with SARS-CoV-2 or a deleterious one, mainly because angiotensin-converting enzyme inhibitor (ACEI) and angiotensin-receptor blocker (ARB) 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 coronavirus disease 2019 (COVID-19) patients 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 by reducing ACE2 receptor effectiveness and mitigating SARS-CoV-2 infectivity. The mechanism for 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 arisen whether using antihypertensive medications will have a favorable impact on people infected with SARS-CoV-2 or a deleterious one, mainly because angiotensin-converting enzyme inhibitor (ACEI) and angiotensin-receptor blocker (ARB) 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 coronavirus disease 2019 (COVID-19) patients 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 by reducing ACE2 receptor effectiveness and mitigating SARS-CoV-2 infectivity. Coronavirus disease 2019 (COVID-19) is an ongoing pandemic of acute respiratory disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The mortality rates, as well as the infectious capacity of the virus, ranging from 1% to >5%, have raised a major concern worldwide. Older people with comorbid conditions, such as pulmonary disease, cardiac disease, kidney disease, diabetes, and hypertension, are associated with higher mortality rates.1Guan W.J. Liang W.H. Zhao Y. Liang H.R. Chen Z.S. Li Y.M. Liu X.Q. Chen R.C. Tang C.L. Wang T. et al.China Medical Treatment Expert Group for COVID-19Comorbidity and its impact on 1590 patients with COVID-19 in China: a nationwide analysis.Eur. Respir. J. 2020; 55: 2000547Crossref PubMed Scopus (8) Google Scholar According to recent literature reports, it is now well accepted that hypertension is associated with increased mortality rates in COVID-19 patients. For example, Wu et al.2Wu C. Chen X. Cai Y. Xia J. Zhou X. Xu S. Huang H. Zhang L. Zhou X. Du C. et al.Risk Factors Associated With Acute Respiratory Distress Syndrome and Death in Patients With Coronavirus Disease 2019 Pneumonia in Wuhan, China.JAMA Intern. Med. 2020; (Published online March 13, 2020)https://doi.org/10.1001/jamainternmed.2020.0994Crossref Scopus (5832) Google Scholar found hypertension to have a hazard ratio of 1.70 for death and 1.82 for acute respiratory distress syndrome (ARDS) in 201 patients with COVID-19. Zhou et al.3Zhou F. Yu T. Du R. Fan G. Liu Y. Liu Z. Xiang J. Wang Y. Song B. Gu X. et al.Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study.Lancet. 2020; 395: 1054-1062Abstract Full Text Full Text PDF PubMed Scopus (18928) Google Scholar also found hypertension to have a hazard ratio of 3.05 for in-hospital mortality in 191 patients with COVID-19. The mechanism for SARS-CoV-2 infection necessitates the binding of the virus to the membrane-bound form of angiotensin-converting enzyme 2 (ACE2) receptor and internalization of the complex by the host cell (Figure 1). Apart from its role as a receptor for SARS-CoV-2 (and for both the SARS-CoV and the related human respiratory coronavirus NL63), ACE2 is well-known for its role in hypertension. ACE2 modulates blood pressure and maintains blood pressure homeostasis through negatively regulating the renin-angiotensin system (RAS).4Li J. Wang X. Chen J. Zhang H. Deng A. 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.JAMA Cardiol. 2020; (Published online April 23, 2020)https://doi.org/10.1001/jamacardio.2020.1624Crossref Scopus (409) Google Scholar,5Reynolds H.R. Adhikari S. Pulgarin C. Troxel A.B. Iturrate E. Johnson S.B. Hausvater A. Newman J.D. Berger J.S. Bangalore S. et al.Renin-Angiotensin-Aldosterone System Inhibitors and Risk of Covid-19.N. Engl. J. Med. 2020; 382: 2441-2448Crossref PubMed Scopus (844) Google Scholar ACE and its homolog ACE2 are two key enzymes involved in the synthesis of bioactive components of the RAS.6Gaddam R.R. Chambers S. Bhatia M. ACE and ACE2 in inflammation: a tale of two enzymes.Inflamm. Allergy Drug Targets. 2014; 13: 224-234Crossref PubMed Scopus (117) Google Scholar ACE2 exerts its functions through cleaving either angiotensin I (Ang I) or Ang II into the inactive peptides Ang (1–9) and Ang (1–7), respectively (Figure 1). Ang (1–9) gets further metabolized into Ang (1–7). Ang (1–7) is a vasodilator, hence ACE2 counteracts the vasoconstrictor effects of the ACE-Ang II axis. The mechanism by which ACE2 antagonizes the effects of Ang II is either by cleaving the precursor Ang I, which reduces Ang II synthesis in tissues, or by directly hydrolyzing Ang II and reducing its levels in plasma. Both ACE and ACE2 are endothelium-bound carboxypeptidases that can be cleaved by different metalloproteases located on the cell surface and released in a soluble form. Contrary to ACE, which is widely expressed in many tissues and organs, ACE2's high expression is confined to the endothelial cells of the arteries, arterioles, and venules of the heart and kidney.4Li J. Wang X. Chen J. Zhang H. Deng A. 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.JAMA Cardiol. 2020; (Published online April 23, 2020)https://doi.org/10.1001/jamacardio.2020.1624Crossref Scopus (409) Google Scholar Therefore, ACE2 has been a potential therapeutic target in treating hypertension and cardiac dysfunctions. Several animal studies, carried out on diet-induced hypertension rat models, have established a link between increased blood pressure and reduced mRNA expression and protein levels of ACE2. Data showed that low levels of ACE2 can lead to elevated levels of Ang II and consequently hypertension.4Li J. Wang X. Chen J. Zhang H. Deng A. 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.JAMA Cardiol. 2020; (Published online April 23, 2020)https://doi.org/10.1001/jamacardio.2020.1624Crossref Scopus (409) Google Scholar Animal studies have suggested that ACE inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) may upregulate ACE2 expression, thus increasing the availability of target molecules for SARS-CoV-2. The Leeds Family Study by Rice et al.7Rice G.I. Jones A.L. Grant P.J. Carter A.M. Turner A.J. Hooper N.M. Circulating activities of angiotensin-converting enzyme, its homolog, angiotensin-converting enzyme 2, and neprilysin in a family study.Hypertension. 2006; 48: 914-920Crossref PubMed Scopus (149) Google Scholar is one of the first studies to demonstrate the link of ACE2 polymorphisms and inheritance of hypertension and levels of circulating ACE2. Several genetic association studies have examined the relationship between ACE2 genetic variants and the risk of developing hypertension in different ethnic populations (Table 1).8Devaux C.A. Rolain J.M. Raoult D. ACE2 receptor polymorphism: Susceptibility to SARS-CoV-2, hypertension, multi-organ failure, and COVID-19 disease outcome.J. Microbiol. Immunol. Infect. 2020; 53: 425-435Crossref PubMed Scopus (363) Google Scholar One of the highly reported variants is rs2285666; AG genotype at this variant is protective because it poses a lower risk to develop hypertension in females.9Vangjeli C. Dicker P. Tregouet D.A. Shields D.C. Evans A. Stanton A.V. MORGAM projectA polymorphism in ACE2 is associated with a lower risk for fatal cardiovascular events in females: the MORGAM project.J. Renin Angiotensin Aldosterone Syst. 2011; 12: 504-509Crossref PubMed Scopus (25) Google Scholar,10Zhang Q. Cong M. Wang N. Li X. Zhang H. Zhang K. Jin M. Wu N. Qiu C. Li J. Association of angiotensin-converting enzyme 2 gene polymorphism and enzymatic activity with essential hypertension in different gender: A case-control study.Medicine (Baltimore). 2018; 97: e12917Crossref PubMed Scopus (68) Google Scholar In contrast, AA genotype, as opposed to AG+GG at the same single-nucleotide polymorphism (SNP) rs2285666, has been reported to be associated with a higher risk of hypertension in different ethnic populations.11Zhong J. Yan Z. Liu D. Ni Y. Zhao Z. Zhu S. Tepel M. Zhu Z. Association of angiotensin-converting enzyme 2 gene A/G polymorphism and elevated blood pressure in Chinese patients with metabolic syndrome.J. Lab. Clin. Med. 2006; 147: 91-95Abstract Full Text Full Text PDF PubMed Scopus (55) Google Scholar, 12Niu W. Qi Y. Hou S. Zhou W. Qiu C. Correlation of angiotensin-converting enzyme 2 gene polymorphisms with stage 2 hypertension in Han Chinese.Transl. Res. 2007; 150: 374-380Abstract Full Text Full Text PDF PubMed Scopus (50) Google Scholar, 13Lu N. Yang Y. Wang Y. Liu Y. Fu G. Chen D. Dai H. Fan X. Hui R. Zheng Y. ACE2 gene polymorphism and essential hypertension: an updated meta-analysis involving 11,051 subjects.Mol. Biol. Rep. 2012; 39: 6581-6589Crossref PubMed Scopus (62) Google Scholar Other highly reported variants known to be associated with high risk to develop hypertension are rs2106809 with TT genotype and rs879922 with C allele.10Zhang Q. Cong M. Wang N. Li X. Zhang H. Zhang K. Jin M. Wu N. Qiu C. Li J. Association of angiotensin-converting enzyme 2 gene polymorphism and enzymatic activity with essential hypertension in different gender: A case-control study.Medicine (Baltimore). 2018; 97: e12917Crossref PubMed Scopus (68) Google Scholar,14Liu D. Chen Y. Zhang P. Zhong J. Jin L. Zhang C. Lin S. Wu S. Yu H. Association between circulating levels of ACE2-Ang-(1-7)-MAS axis and ACE2 gene polymorphisms in hypertensive patients.Medicine (Baltimore). 2016; 95: e3876Crossref PubMed Scopus (36) Google Scholar, 15Patnaik M. Pati P. Swain S.N. Mohapatra M.K. Dwibedi B. Kar S.K. Ranjit M. Association of angiotensin-converting enzyme and angiotensin-converting enzyme-2 gene polymorphisms with essential hypertension in the population of Odisha, India.Ann. Hum. Biol. 2014; 41: 145-152Crossref PubMed Scopus (47) Google Scholar, 16Wang S.X. Fu C.Y. Zou Y.B. Wang H. Shi Y. Xu X.Q. Chen J.Z. Song X.D. Huan T.J. Hui R.T. Polymorphisms of angiotensin-converting enzyme 2 gene associated with magnitude of left ventricular hypertrophy in male patients with hypertrophic cardiomyopathy.Chin. Med. J. (Engl.). 2008; 121: 27-31Crossref PubMed Google Scholar, 17Pan Y. Wang T. Li Y. Guan T. Lai Y. Shen Y. Zeyaweiding A. Maimaiti T. Li F. Zhao H. Liu C. Association of ACE2 polymorphisms with susceptibility to essential hypertension and dyslipidemia in Xinjiang, China.Lipids Health Dis. 2018; 17: 241Crossref PubMed Scopus (58) Google Scholar, 18Luo Y. Liu C. Guan T. Li Y. Lai Y. Li F. Zhao H. Maimaiti T. Zeyaweiding A. Association of ACE2 genetic polymorphisms with hypertension-related target organ damages in south Xinjiang.Hypertens. Res. 2019; 42: 681-689Crossref PubMed Scopus (73) Google Scholar However, the European population study revealed the absence of an association between rs879922 and high blood pressure.19Lieb W. Graf J. Götz A. König I.R. Mayer B. Fischer M. Stritzke J. Hengstenberg C. Holmer S.R. Döring A. et al.Association of angiotensin-converting enzyme 2 (ACE2) gene polymorphisms with parameters of left ventricular hypertrophy in men. Results of the MONICA Augsburg echocardiographic substudy.J. Mol. Med. (Berl.). 2006; 84: 88-96Crossref PubMed Scopus (96) Google Scholar Further, although there are several genetic studies on ACE2's role in hypertension using different continental populations (such as China, Europe, Australia, and India), ethnic populations such as from the Middle East are not included in these global studies. Thus, genetic association data involving ACE2 with hypertension have been debatable in terms of transferability across different ethnicities.Table 1Reported ACE2 Polymorphisms Associated with the Risk of Hypertension and/or Cardiovascular Disease in Different Populations/EthnicitiesPolymorphism IDAllele and/or GenotypeEthnicity/Population SizeAssociated Predisposition to HypertensionPublicationsrs4646188TChinahigh17Pan Y. Wang T. Li Y. Guan T. Lai Y. Shen Y. Zeyaweiding A. Maimaiti T. Li F. Zhao H. Liu C. Association of ACE2 polymorphisms with susceptibility to essential hypertension and dyslipidemia in Xinjiang, China.Lipids Health Dis. 2018; 17: 241Crossref PubMed Scopus (58) Google Scholar,18Luo Y. Liu C. Guan T. Li Y. Lai Y. Li F. Zhao H. Maimaiti T. Zeyaweiding A. Association of ACE2 genetic polymorphisms with hypertension-related target organ damages in south Xinjiang.Hypertens. Res. 2019; 42: 681-689Crossref PubMed Scopus (73) Google Scholarrs2074192TChinahigh17Pan Y. Wang T. Li Y. Guan T. Lai Y. Shen Y. Zeyaweiding A. Maimaiti T. Li F. Zhao H. Liu C. Association of ACE2 polymorphisms with susceptibility to essential hypertension and dyslipidemia in Xinjiang, China.Lipids Health Dis. 2018; 17: 241Crossref PubMed Scopus (58) Google Scholar,18Luo Y. Liu C. Guan T. Li Y. Lai Y. Li F. Zhao H. Maimaiti T. Zeyaweiding A. Association of ACE2 genetic polymorphisms with hypertension-related target organ damages in south Xinjiang.Hypertens. Res. 2019; 42: 681-689Crossref PubMed Scopus (73) Google Scholar,32Chen Y.Y. Zhang P. Zhou X.M. Liu D. Zhong J.C. Zhang C.J. Jin L.J. Yu H.M. Relationship between genetic variants of ACE2 gene and circulating levels of ACE2 and its metabolites.J. Clin. Pharm. Ther. 2018; 43: 189-195Crossref PubMed Scopus (46) Google Scholarrs4646155T, TTChinahigh10Zhang Q. Cong M. Wang N. Li X. Zhang H. Zhang K. Jin M. Wu N. Qiu C. Li J. Association of angiotensin-converting enzyme 2 gene polymorphism and enzymatic activity with essential hypertension in different gender: A case-control study.Medicine (Baltimore). 2018; 97: e12917Crossref PubMed Scopus (68) Google Scholar,17Pan Y. Wang T. Li Y. Guan T. Lai Y. Shen Y. Zeyaweiding A. Maimaiti T. Li F. Zhao H. Liu C. Association of ACE2 polymorphisms with susceptibility to essential hypertension and dyslipidemia in Xinjiang, China.Lipids Health Dis. 2018; 17: 241Crossref PubMed Scopus (58) Google Scholar,18Luo Y. Liu C. Guan T. Li Y. Lai Y. Li F. Zhao H. Maimaiti T. Zeyaweiding A. Association of ACE2 genetic polymorphisms with hypertension-related target organ damages in south Xinjiang.Hypertens. Res. 2019; 42: 681-689Crossref PubMed Scopus (73) Google Scholarrs4240157CChinahigh17Pan Y. Wang T. Li Y. Guan T. Lai Y. Shen Y. Zeyaweiding A. Maimaiti T. Li F. Zhao H. Liu C. Association of ACE2 polymorphisms with susceptibility to essential hypertension and dyslipidemia in Xinjiang, China.Lipids Health Dis. 2018; 17: 241Crossref PubMed Scopus (58) Google Scholar,18Luo Y. Liu C. Guan T. Li Y. Lai Y. Li F. Zhao H. Maimaiti T. Zeyaweiding A. Association of ACE2 genetic polymorphisms with hypertension-related target organ damages in south Xinjiang.Hypertens. Res. 2019; 42: 681-689Crossref PubMed Scopus (73) Google Scholarrs4830542CChinahigh17Pan Y. Wang T. Li Y. Guan T. Lai Y. Shen Y. Zeyaweiding A. Maimaiti T. Li F. Zhao H. Liu C. Association of ACE2 polymorphisms with susceptibility to essential hypertension and dyslipidemia in Xinjiang, China.Lipids Health Dis. 2018; 17: 241Crossref PubMed Scopus (58) Google Scholar,18Luo Y. Liu C. Guan T. Li Y. Lai Y. Li F. Zhao H. Maimaiti T. Zeyaweiding A. Association of ACE2 genetic polymorphisms with hypertension-related target organ damages in south Xinjiang.Hypertens. Res. 2019; 42: 681-689Crossref PubMed Scopus (73) Google Scholarrs879922CChinahigh10Zhang Q. Cong M. Wang N. Li X. Zhang H. Zhang K. Jin M. Wu N. Qiu C. Li J. Association of angiotensin-converting enzyme 2 gene polymorphism and enzymatic activity with essential hypertension in different gender: A case-control study.Medicine (Baltimore). 2018; 97: e12917Crossref PubMed Scopus (68) Google Scholar,17Pan Y. Wang T. Li Y. Guan T. Lai Y. Shen Y. Zeyaweiding A. Maimaiti T. Li F. Zhao H. Liu C. Association of ACE2 polymorphisms with susceptibility to essential hypertension and dyslipidemia in Xinjiang, China.Lipids Health Dis. 2018; 17: 241Crossref PubMed Scopus (58) Google Scholar,18Luo Y. Liu C. Guan T. Li Y. Lai Y. Li F. Zhao H. Maimaiti T. Zeyaweiding A. Association of ACE2 genetic polymorphisms with hypertension-related target organ damages in south Xinjiang.Hypertens. Res. 2019; 42: 681-689Crossref PubMed Scopus (73) Google Scholarrs2106809TT, TChina, Indiahigh14Liu D. Chen Y. Zhang P. Zhong J. Jin L. Zhang C. Lin S. Wu S. Yu H. Association between circulating levels of ACE2-Ang-(1-7)-MAS axis and ACE2 gene polymorphisms in hypertensive patients.Medicine (Baltimore). 2016; 95: e3876Crossref PubMed Scopus (36) Google Scholar, 15Patnaik M. Pati P. Swain S.N. Mohapatra M.K. Dwibedi B. Kar S.K. Ranjit M. Association of angiotensin-converting enzyme and angiotensin-converting enzyme-2 gene polymorphisms with essential hypertension in the population of Odisha, India.Ann. Hum. Biol. 2014; 41: 145-152Crossref PubMed Scopus (47) Google Scholar, 16Wang S.X. Fu C.Y. Zou Y.B. Wang H. Shi Y. Xu X.Q. Chen J.Z. Song X.D. Huan T.J. Hui R.T. Polymorphisms of angiotensin-converting enzyme 2 gene associated with magnitude of left ventricular hypertrophy in male patients with hypertrophic cardiomyopathy.Chin. Med. J. (Engl.). 2008; 121: 27-31Crossref PubMed Google Scholar, 17Pan Y. Wang T. Li Y. Guan T. Lai Y. Shen Y. Zeyaweiding A. Maimaiti T. Li F. Zhao H. Liu C. Association of ACE2 polymorphisms with susceptibility to essential hypertension and dyslipidemia in Xinjiang, China.Lipids Health Dis. 2018; 17: 241Crossref PubMed Scopus (58) Google Scholar, 18Luo Y. Liu C. Guan T. Li Y. Lai Y. Li F. Zhao H. Maimaiti T. Zeyaweiding A. Association of ACE2 genetic polymorphisms with hypertension-related target organ damages in south Xinjiang.Hypertens. Res. 2019; 42: 681-689Crossref PubMed Scopus (73) Google Scholar,32Chen Y.Y. Zhang P. Zhou X.M. Liu D. Zhong J.C. Zhang C.J. Jin L.J. Yu H.M. Relationship between genetic variants of ACE2 gene and circulating levels of ACE2 and its metabolites.J. Clin. Pharm. Ther. 2018; 43: 189-195Crossref PubMed Scopus (46) Google Scholarrs2285666A, TC, G, AAEurope metaanalysis (five cohorts: ATBC, FINRISK, Northern Sweden, PRIME/Belfast, and PRIME/France), Chinalow (preventive)9Vangjeli C. Dicker P. Tregouet D.A. Shields D.C. Evans A. Stanton A.V. MORGAM projectA polymorphism in ACE2 is associated with a lower risk for fatal cardiovascular events in females: the MORGAM project.J. Renin Angiotensin Aldosterone Syst. 2011; 12: 504-509Crossref PubMed Scopus (25) Google Scholar,10Zhang Q. Cong M. Wang N. Li X. Zhang H. Zhang K. Jin M. Wu N. Qiu C. Li J. Association of angiotensin-converting enzyme 2 gene polymorphism and enzymatic activity with essential hypertension in different gender: A case-control study.Medicine (Baltimore). 2018; 97: e12917Crossref PubMed Scopus (68) Google Scholarrs2285666GG, AAEurope, meta-analysis (China, Anglo Celtic Australian)high11Zhong J. Yan Z. Liu D. Ni Y. Zhao Z. Zhu S. Tepel M. Zhu Z. Association of angiotensin-converting enzyme 2 gene A/G polymorphism and elevated blood pressure in Chinese patients with metabolic syndrome.J. Lab. Clin. Med. 2006; 147: 91-95Abstract Full Text Full Text PDF PubMed Scopus (55) Google Scholar, 12Niu W. Qi Y. Hou S. Zhou W. Qiu C. Correlation of angiotensin-converting enzyme 2 gene polymorphisms with stage 2 hypertension in Han Chinese.Transl. Res. 2007; 150: 374-380Abstract Full Text Full Text PDF PubMed Scopus (50) Google Scholar, 13Lu N. Yang Y. Wang Y. Liu Y. Fu G. Chen D. Dai H. Fan X. Hui R. Zheng Y. ACE2 gene polymorphism and essential hypertension: an updated meta-analysis involving 11,051 subjects.Mol. Biol. Rep. 2012; 39: 6581-6589Crossref PubMed Scopus (62) Google Scholarrs1514283CCChinahigh10Zhang Q. Cong M. Wang N. Li X. Zhang H. Zhang K. Jin M. Wu N. Qiu C. Li J. Association of angiotensin-converting enzyme 2 gene polymorphism and enzymatic activity with essential hypertension in different gender: A case-control study.Medicine (Baltimore). 2018; 97: e12917Crossref PubMed Scopus (68) Google Scholarrs4646176GGChinahigh10Zhang Q. Cong M. Wang N. Li X. Zhang H. Zhang K. Jin M. Wu N. Qiu C. Li J. Association of angiotensin-converting enzyme 2 gene polymorphism and enzymatic activity with essential hypertension in different gender: A case-control study.Medicine (Baltimore). 2018; 97: e12917Crossref PubMed Scopus (68) Google ScholarA1075G (rs1978124)GGChina, Europe, meta-analysis (China, Anglo Celtic Australian)high12Niu W. Qi Y. Hou S. Zhou W. Qiu C. Correlation of angiotensin-converting enzyme 2 gene polymorphisms with stage 2 hypertension in Han Chinese.Transl. Res. 2007; 150: 374-380Abstract Full Text Full Text PDF PubMed Scopus (50) Google Scholar,40Benjafield A.V. Wang W.Y.S. Morris B.J. No association of angiotensin-converting enzyme 2 gene (ACE2) polymorphisms with essential hypertension.Am. J. Hypertens. 2004; 17: 624-628Crossref PubMed Scopus (72) Google Scholar,41Palmer B.R. Jarvis M.D. Pilbrow A.P. Ellis K.L. Frampton C.M. Skelton L. Yandle T.G. Doughty R.N. Whalley G.A. Ellis C.J. et al.Angiotensin-converting enzyme 2 A1075G polymorphism is associated with survival in an acute coronary syndromes cohort.Am. Heart J. 2008; 156: 752-758Crossref PubMed Scopus (23) Google Scholarrs6632677CChinahigh42Wang S. Fu C. Zou Y. Wang H. Shi Y. Xu X. Chen J. Song X. Huan T. Hui R. Polymorphisms of angiotensin-converting enzyme 2 gene associated with magnitude of left ventricular hypertrophy in male patients with hypertrophic cardiomyopathy.Chin. Med. J. (Engl). 2008; 121: 27-31Crossref PubMed Scopus (27) Google Scholar Open table in a new tab Importantly, ACE2 is currently at the center of an intense debate among cardiologists; there are concerns on whether medical management of hypertension involving the use of inhibitors of the renin-angiotensin-aldosterone system (RAAS) (such as ACEIs and ARBs) have a favorable impact on people infected with SARS-CoV-2 or a deleterious one mainly because ACEI and ARB therapies can modulate the expression of ACE2. 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. As a result, there has been a call for the discontinuation of ACEI/ARB usage prophylactically and in the context of suspected COVID-19 cases. In this review, we shed light on the current debate about ACE2's role in the mortality associated with COVID-19 cases with hypertension and weigh on the current argument about the usage or discontinuation of ACEI/ARB hypertensive medication. Finally, we explore the role of ACE2 genetic variants in the predisposition for hypertension and the response to hypertension treatments. Several epidemiological studies have established the augmented mortality in COVID-19 patients with hypertension. For instance, Wu et al.2Wu C. Chen X. Cai Y. Xia J. Zhou X. Xu S. Huang H. Zhang L. Zhou X. Du C. et al.Risk Factors Associated With Acute Respiratory Distress Syndrome and Death in Patients With Coronavirus Disease 2019 Pneumonia in Wuhan, China.JAMA Intern. Med. 2020; (Published online March 13, 2020)https://doi.org/10.1001/jamainternmed.2020.0994Crossref Scopus (5832) Google Scholar and Zhou et al.3Zhou F. Yu T. Du R. Fan G. Liu Y. Liu Z. Xiang J. Wang Y. Song B. Gu X. et al.Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study.Lancet. 2020; 395: 1054-1062Abstract Full Text Full Text PDF PubMed Scopus (18928) Google Scholar had found hypertension to have a hazard ratio of 1.70 and 3.05 for death in 201 and 191 patients with COVID-19, respectively. However, a critical question that remains unanswered is whether this association is solely attributed to the pathogenesis of hypertension or to the associated comorbidity or therapy. In this section, we review recent findings regarding the role of antihypertensive medications, which have been at the center of a considerable debate, namely, ACEIs and ARBs. The main question has been whether they have a favorable impact on the people infected with SARS-CoV-2 or a deleterious one mainly because ACEI and ARB therapies can modulate the expression of ACE2, which has been identified as a receptor for SARS-COV2. 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. As a result, there has been a call for the discontinuation of ACEIs/ARBs usage prophylactically and in the context of suspected COVID-19. However, other groups have been suggesting the opposite, where increased ACE2 can act as a vasodilator, antioxidant, and anti-inflammatory. This is because ACE2 primarily acts to counterpoise the effect of ACE. Because ACE produces Ang II from Ang I, ACE2 generates Ang (1–9) from Ang I or Ang (1–7) from Ang II, respectively. Ang (1–7) possesses vasodilator, antioxidant, and anti-inflammatory properties that, upon binding to the Mas receptor broadly, shifts the balance from vasoconstriction with Ang II to vasodilation with Mas receptor activation in the affected vascular bed.20Santos R.A. Angiotensin-(1-7).Hypertension. 2014; 63: 1138-1147Crossref PubMed Scopus (191) Google Scholar,21El-Hashim A.Z. Renno W.M. Raghupathy R. Abduo H.T. Akhtar S. Benter I.F. Angiotensin-(1-7) inhibits allergic inflammation, via the MAS1 receptor, through suppression of ERK1/2- and NF-κB-dependent pathways.Br. J. Pharmacol. 2012; 166: 1964-1976Crossref PubMed Scopus (126) Google Scholar The role this vasodilatory effect has in the pathogenesis of SARS-CoV-2 is unclear, but some animal data suggest a connection. ACE2 and Ang (1–7) are protective in several different lung injury models. Despite the lack of evidence, there have been advocates for both the use and the cessation of ACEIs, ARBs, or both during the treatment for COVID-19 in patients with hypertension.5Reynolds H.R. Adhikari S. Pulgarin C. Troxel A.B. Iturrate E. Johnson S.B. Hausvater A. Newman J.D. Berger J.S. Bangalore S. et al.Renin-Angiotensin-Aldosterone System Inhibitors and Risk of Covid-19.N. Engl. J. Med. 2020; 382: 2441-2448Crossref PubMed Scopus (844) Google Scholar Given the common use of ACEIs and ARBs worldwide, guidance based on experimental evidence on the use of these drugs in patients with COVID-19 is immensely needed. A few studies have emerged that tackled this question, providing initial data to answer this question. In one retrospective single-center case series study of 1,178 COVID-19 cases, Li et al.4Li J. Wang X. Chen J. Zhang H. Deng A. 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.JAMA Cardiol. 2020; (Published online April 23, 2020)https://doi.org/10.1001/jamacardio.2020.1624Crossref Scopus (409) Google Scholar examined the association between the severity and mortality of COVID-19 and antihypertensive medications ACEIs or ARBs. A total of 362 patients were hypertensive and 115 patients were treated with ACEIs or ARBs. The authors observed no difference in the severity of COVID-19, as well as mortality rates between the people taking ACEIs or ARBs or not. Similarly, there was no difference in severity or mortality rates between patients taking ACEIs and those taking ARBs.4Li J. Wang X. Chen J. Zhang H. Deng A. 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.JAMA Cardiol. 2020; (Published online April 23, 2020)https:/