Generic placeholder image

Current Hypertension Reviews


ISSN (Print): 1573-4021
ISSN (Online): 1875-6506

Mini-Review Article

COVID-19, Angiotensin-Converting Enzyme 2 and Renin-Angiotensin System Inhibition: Implications for Practice

Author(s): Vasiliki Katsi, George Pavlidis*, George Charalambous, Dimitrios Tousoulis and Konstantinos Toutouzas

Volume 18, Issue 1, 2022

Published on: 21 January, 2021

Page: [3 - 10] Pages: 8

DOI: 10.2174/1573402117666210121100201

Price: $65


Background: Recent studies suggested that patients with coronavirus disease 2019 (COVID-19) who use renin-angiotensin system (RAS) inhibitors have an increased risk of respiratory failure and death. The hypothesis was that angiotensin-converting enzyme inhibitor (ACEIs) or angiotensin receptor blocker (ARBs) might up-regulate ACE2 expression that is used as a receptor for viral entry into cells.

Objective: The purpose of this review is to discuss the existing evidence on the interaction between COVID-19 infection, ACE2 and ACEIs or ARBs and to examine the main implications for clinical practice. In addition, novel therapeutic strategies for blocking ACE2-mediated COVID-19 infection will be displayed.

Methods: We performed a comprehensive review of the literature to identify data from clinical and experimental studies for the association between COVID-19 infection, ACE2 and RAS inhibition.

Results: The current clinical and experimental evidence for ACEIs or ARBs to facilitate severe acute respiratory distress syndrome-coronavirus-2 (SARS-CoV-2) is insufficient to suggest discontinuing these drugs. Several observational studies arrive at the conclusion that the continued use of RAS inhibitors is unlikely to be harmful in COVID-19-positive patients.

Conclusions: Further randomized trials are needed to answer the question of whether RAS inhibitors are harmful or beneficial to patients with COVID-19.

Keywords: COVID-19, hypertension, angiotensin-converting enzyme 2, renin-angiotensin system, an angiotensin-converting enzyme inhibitor, angiotensin receptor blocker.

Graphical Abstract
Williams B, Mancia G, Spiering W, et al. 2018 ESC/ESH Guidelines for the management of arterial hypertension. Eur Heart J 2018; 39(33): 3021-104.
[] [PMID: 30165516]
Fisher D, Heymann D. Q&A: The novel coronavirus outbreak causing COVID-19. BMC Med 2020; 18(1): 57.
[] [PMID: 32106852]
Zhou F, Yu T, Du R, 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(10229): 1054-62.
[] [PMID: 32171076]
Turner AJ, Hiscox JA, Hooper NM. ACE2: from vasopeptidase to SARS virus receptor. Trends Pharmacol Sci 2004; 25(6): 291-4.
[] [PMID: 15165741]
Li W, Moore MJ, Vasilieva N, et al. Angiotensin-converting enzyme 2 is a functional receptor for the SARS coronavirus. Nature 2003; 426(6965): 450-4.
[] [PMID: 14647384]
European Society of Cardiology. Position statement of the ESC Council on Hypertension on ACE-inhibitors and angiotensin receptor blockers
American College of Cardiology. HFSA/ACC/AHA statement addresses concerns re: using RAAS antagonists in COVID-19
Vaduganathan M, Vardeny O, Michel T, McMurray JJV, Pfeffer MA, Solomon SD. Renin-angiotensin-aldosterone system inhibitors in patients with Covid-19. N Engl J Med 2020; 382(17): 1653-9.
[] [PMID: 32227760]
Shibata S, Arima H, Asayama K, et al. Hypertension and related diseases in the era of COVID-19: a report from the Japanese Society of Hypertension Task Force on COVID-19. Hypertens Res 2020; 43(10): 1028-46.
[] [PMID: 32737423]
Ghazi L, Drawz P. Advances in understanding the renin-angiotensin-aldosterone system (RAAS) in blood pressure control and recent pivotal trials of RAAS blockade in heart failure and diabetic nephropathy. F1000Res 6 pii: F1000 Faculty Rev-297 2017.
Tikellis C, Thomas MC. Angiotensin-converting enzyme 2 (ACE2) is a key modulator of the renin angiotensin system in health and disease. Int J Pept 2012; 2012
[] [PMID: 22536270]
Tan WSD, Liao W, Zhou S, Mei D, Wong WF. Targeting the renin-angiotensin system as novel therapeutic strategy for pulmonary diseases. Curr Opin Pharmacol 2018; 40: 9-17.
[] [PMID: 29288933]
Kuba K, Imai Y, Penninger JM. Multiple functions of angiotensin-converting enzyme 2 and its relevance in cardiovascular diseases. Circ J 2013; 77(2): 301-8.
[] [PMID: 23328447]
Perlot T, Penninger JM. ACE2 - from the renin-angiotensin system to gut microbiota and malnutrition. Microbes Infect 2013; 15(13): 866-73.
[] [PMID: 23962453]
Kuba K, Imai Y, Ohto-Nakanishi T, Penninger JM. Trilogy of ACE2: a peptidase in the renin-angiotensin system, a SARS receptor, and a partner for amino acid transporters. Pharmacol Ther 2010; 128(1): 119-28.
[] [PMID: 20599443]
Balakumar P, Jagadeesh G. A century old renin-angiotensin system still grows with endless possibilities: AT1 receptor signaling cascades in cardiovascular physiopathology. Cell Signal 2014; 26(10): 2147-60.
[] [PMID: 25007996]
Strawn WB, Ferrario CM. Mechanisms linking angiotensin II and atherogenesis. Curr Opin Lipidol 2002; 13(5): 505-12.
[] [PMID: 12352014]
Dandona P, Dhindsa S, Ghanim H, Chaudhuri A. Angiotensin II and inflammation: the effect of angiotensin-converting enzyme inhibition and angiotensin II receptor blockade. J Hum Hypertens 2007; 21(1): 20-7.
[] [PMID: 17096009]
Chappell MC, Al Zayadneh EM. Angiotensin-(1-7) and the regulation of anti-fibrotic signaling pathways. J Cell Signal 2017; 2(1): 134.
[] [PMID: 28691117]
Carey RM, Padia SH. Angiotensin AT2 receptors: control of renal sodium excretion and blood pressure. Trends Endocrinol Metab 2008; 19(3): 84-7.
[] [PMID: 18294862]
Jones ES, Vinh A, McCarthy CA, Gaspari TA, Widdop RE. AT2 receptors: functional relevance in cardiovascular disease. Pharmacol Ther 2008; 120(3): 292-316.
[] [PMID: 18804122]
Nehme A, Zouein FA, Zayeri ZD, Zibara K. An update on the tissue renin angiotensin system and its role in physiology and pathology. J Cardiovasc Dev Dis 2019; 6(2): 14.
[] [PMID: 30934934]
Tipnis SR, Hooper NM, Hyde R, Karran E, Christie G, Turner AJ. A human homolog of angiotensin-converting enzyme. Cloning and functional expression as a captopril-insensitive carboxypeptidase. J Biol Chem 2000; 275(43): 33238-43.
[] [PMID: 10924499]
Lambert DW, Yarski M, Warner FJ, et al. Tumor necrosis factor-alpha convertase (ADAM17) mediates regulated ectodomain shedding of the severe-acute respiratory syndrome-coronavirus (SARS-CoV) receptor, angiotensin-converting enzyme-2 (ACE2). J Biol Chem 2005; 280(34): 30113-9.
[] [PMID: 15983030]
Hamming I, Timens W, Bulthuis ML, Lely AT, Navis G, van Goor H. Tissue distribution of ACE2 protein, the functional receptor for SARS coronavirus. A first step in understanding SARS pathogenesis. J Pathol 2004; 203(2): 631-7.
[] [PMID: 15141377]
Hofmann H, Pöhlmann S. Cellular entry of the SARS coronavirus. Trends Microbiol 2004; 12(10): 466-72.
[] [PMID: 15381196]
Wang Z, Xu X. scRNA-seq profiling of human testes reveals the presence of the ACE2 receptor, a target for SARS-CoV-2 infection in spermatogonia, Leydig and Sertoli cells. Cells 2020; 9(4): 920.
[] [PMID: 32283711]
Vickers C, Hales P, Kaushik V, et al. Hydrolysis of biological peptides by human angiotensin-converting enzyme-related carboxypeptidase. J Biol Chem 2002; 277(17): 14838-43.
[] [PMID: 11815627]
Santos RA, Ferreira AJ, Verano-Braga T, Bader M. Angiotensin- converting enzyme 2, angiotensin-(1-7) and Mas: new players of the renin-angiotensin system. J Endocrinol 2013; 216(2): R1-R17.
[] [PMID: 23092879]
Santos RAS, Sampaio WO, Alzamora AC, et al. The ACE2/angiotensin-(1-7)/MAS axis of the renin-angiotensin system: focus on angiotensin-(1-7). Physiol Rev 2018; 98(1): 505-53.
[] [PMID: 29351514]
Zhang H, Penninger JM, Li Y, Zhong N, Slutsky AS. Angiotensin-converting enzyme 2 (ACE2) as a SARS-CoV-2 receptor: molecular mechanisms and potential therapeutic target. Intensive Care Med 2020; 46(4): 586-90.
[] [PMID: 32125455]
Parajuli N, Ramprasath T, Patel VB, et al. Targeting angiotensin- converting enzyme 2 as a new therapeutic target for cardiovascular diseases. Can J Physiol Pharmacol 2014; 92(7): 558-65.
[] [PMID: 24861775]
Chamsi-Pasha MA, Shao Z, Tang WH. Angiotensin-converting enzyme 2 as a therapeutic target for heart failure. Curr Heart Fail Rep 2014; 11(1): 58-63.
[] [PMID: 24293035]
Raiden S, Nahmod K, Nahmod V, et al. Nonpeptide antagonists of AT1 receptor for angiotensin II delay the onset of acute respiratory distress syndrome. J Pharmacol Exp Ther 2002; 303(1): 45-51.
[] [PMID: 12235231]
Chen M, Chen C, Yuan X, et al. Angiotensin II aggravates lipopolysaccharide induced human pulmonary microvascular endothelial cells permeability in high glucose status. Endocr J 2018; 65(7): 717-25.
[] [PMID: 29709898]
Gurwitz D. Angiotensin receptor blockers as tentative SARS-CoV-2 therapeutics. Drug Dev Res 2020; 81(5): 537-40.
[] [PMID: 32129518]
Stoll D, Yokota R, Sanches Aragão D, Casarini DE. Both aldosterone and spironolactone can modulate the intracellular ACE/ANG II/AT1 and ACE2/ANG (1-7)/MAS receptor axes in human mesangial cells. Physiol Rep 2019; 7(11)
[] [PMID: 31165585]
Ramchand J, Patel SK, Srivastava PM, Farouque O, Burrell LM. Elevated plasma angiotensin converting enzyme 2 activity is an independent predictor of major adverse cardiac events in patients with obstructive coronary artery disease. PLoS One 2018; 13(6)
[] [PMID: 29897923]
Serfozo P, Wysocki J, Gulua G, et al. Ang II (angiotensin II) conversion to angiotensin-(1-7) in the circulation is POP (prolyloligopeptidase)-dependent and ACE2 (Angiotensin-converting enzyme 2)-independent. Hypertension 2020; 75(1): 173-82.
[] [PMID: 31786979]
Rice GI, Jones AL, Grant PJ, Carter AM, Turner AJ, Hooper NM. Circulating activities of angiotensin-converting enzyme, its homolog, angiotensin-converting enzyme 2, and neprilysin in a family study. Hypertension 2006; 48(5): 914-20.
[] [PMID: 17000927]
Wang G, Lai FM, Kwan BC, et al. Expression of ACE and ACE2 in patients with hypertensive nephrosclerosis. Kidney Blood Press Res 2011; 34(3): 141-9.
[] [PMID: 21346373]
Anguiano L, Riera M, Pascual J, et al. NEFRONA study. Circulating angiotensin-converting enzyme 2 activity in patients with chronic kidney disease without previous history of cardiovascular disease. Nephrol Dial Transplant 2015; 30(7): 1176-85.
[] [PMID: 25813276]
Gilbert A, Liu J, Cheng G, et al. A review of urinary angiotensin converting enzyme 2 in diabetes and diabetic nephropathy. Biochem Med (Zagreb) 2019; 29(1)
[] [PMID: 30591810]
Sama IE, Ravera A, Santema BT, et al. Circulating plasma concentrations of angiotensin-converting enzyme 2 in men and women with heart failure and effects of renin-angiotensin-aldosterone inhibitors. Eur Heart J 2020; 41(19): 1810-7.
[] [PMID: 32388565]
Lin B, Ferguson C, White JT, et al. Prostate-localized and androgen-regulated expression of the membrane-bound serine protease TMPRSS2. Cancer Res 1999; 59(17): 4180-4.
[PMID: 10485450]
Antalis TM, Bugge TH, Wu Q. Membrane-anchored serine proteases in health and disease. Prog Mol Biol Transl Sci 2011; 99: 1-50.
[] [PMID: 21238933]
Matsuyama S, Ujike M, Morikawa S, Tashiro M, Taguchi F. Protease-mediated enhancement of severe acute respiratory syndrome coronavirus infection. Proc Natl Acad Sci USA 2005; 102(35): 12543-7.
[] [PMID: 16116101]
Hoffmann M, Kleine-Weber H, Schroeder S, et al. SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor. Cell 2020; 181(2): 271-280.e8.
[] [PMID: 32142651]
Matsuyama S, Nao N, Shirato K, et al. Enhanced isolation of SARS-CoV-2 by TMPRSS2-expressing cells. Proc Natl Acad Sci USA 2020; 117(13): 7001-3.
[] [PMID: 32165541]
Heurich A, Hofmann-Winkler H, Gierer S, Liepold T, Jahn O, Pöhlmann S. TMPRSS2 and ADAM17 cleave ACE2 differentially and only proteolysis by TMPRSS2 augments entry driven by the severe acute respiratory syndrome coronavirus spike protein. J Virol 2014; 88(2): 1293-307.
[] [PMID: 24227843]
Yan T, Xiao R, Lin G. Angiotensin-converting enzyme 2 in severe acute respiratory syndrome coronavirus and SARS-CoV-2: A double-edged sword? FASEB J 2020; 34(5): 6017-26.
[] [PMID: 32306452]
Wang S, Zhou X, Zhang T, Wang Z. The need for urogenital tract monitoring in COVID-19. Nat Rev Urol 2020; 17(6): 314-5.
[] [PMID: 32313110]
Zhao S, Zhu W, Xue S, Han D. Testicular defense systems: immune privilege and innate immunity. Cell Mol Immunol 2014; 11(5): 428-37.
[] [PMID: 24954222]
Ma L, Xie W, Li D, et al. Effect of SARS-CoV-2 infection upon male gonadal function: A single center-based study. medRxiv
Pan F, Xiao X, Guo J, et al. No evidence of SARS-CoV-2 in semen of males recovering from COVID-19. Fertil Steril 2020; 113(6): 1135-9.
[] [PMID: 32482249]
Wu C, Chen X, Cai Y, 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; 180(7): 934-43.
[] [PMID: 32167524]
Guan WJ, Ni ZY, Hu Y, et al. China Medical Treatment Expert Group for Covid-19. China medical treatment expert group for Covid-19. Clinical characteristics of coronavirus disease 2019 in China. N Engl J Med 2020; 382(18): 1708-20.
[] [PMID: 32109013]
Fang L, Karakiulakis G, Roth M. Are patients with hypertension and diabetes mellitus at increased risk for COVID-19 infection? Lancet Respir Med 2020; 8(4)
[] [PMID: 32171062]
Ferrario CM, Jessup J, Chappell MC, et al. Effect of angiotensin- converting enzyme inhibition and angiotensin II receptor blockers on cardiac angiotensin-converting enzyme 2. Circulation 2005; 111(20): 2605-10.
[] [PMID: 15897343]
Walters TE, Kalman JM, Patel SK, Mearns M, Velkoska E, Burrell LM. Angiotensin converting enzyme 2 activity and human atrial fibrillation: increased plasma angiotensin converting enzyme 2 activity is associated with atrial fibrillation and more advanced left atrial structural remodelling. Europace 2017; 19(8): 1280-7.
[PMID: 27738071]
Kuba K, Imai Y, Rao S, et al. A crucial role of angiotensin converting enzyme 2 (ACE2) in SARS coronavirus-induced lung injury. Nat Med 2005; 11(8): 875-9.
[] [PMID: 16007097]
Phadke M, Saunik S. Rapid response: use of angiotensin receptor blockers such as Telmisartan, Losartsan in nCoV Wuhan Corona Virus infections - novel mode of treatment. Response to the emerging novel coronavirus outbreak. BMJ 2020; 368: m40.
Zheng YY, Ma YT, Zhang JY, Xie X. COVID-19 and the cardiovascular system. Nat Rev Cardiol 2020; 17(5): 259-60.
[] [PMID: 32139904]
Imai Y, Kuba K, Rao S, et al. Angiotensin-converting enzyme 2 protects from severe acute lung failure. Nature 2005; 436(7047): 112-6.
[] [PMID: 16001071]
Zou Z, Yan Y, Shu Y, et al. Angiotensin-converting enzyme 2 protects from lethal avian influenza A H5N1 infections. Nat Commun 2014; 5: 3594.
[] [PMID: 24800825]
Yang P, Gu H, Zhao Z, et al. Angiotensin-converting enzyme 2 (ACE2) mediates influenza H7N9 virus-induced acute lung injury. Sci Rep 2014; 4: 7027.
[] [PMID: 25391767]
Li 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; 5(7): 825-30.
[] [PMID: 32324209]
Mehra MR, Desai SS, Kuy S, Henry TD, Patel AN. Cardiovascular disease, drug therapy, and mortality in Covid-19. N Engl J Med 2020; 382(25)
[] [PMID: 32356626]
Mancia G, Rea F, Ludergnani M, Apolone G, Corrao G. Renin-angiotensin-aldosterone system blockers and the risk of Covid-19. N Engl J Med 2020; 382(25): 2431-40.
[] [PMID: 32356627]
Reynolds HR, Adhikari S, Pulgarin C, et al. Renin-angiotensin-aldosterone system inhibitors and risk of Covid-19. N Engl J Med 2020; 382(25): 2441-8.
[] [PMID: 32356628]
Fosbøl EL, Butt JH, Østergaard L, et al. Association of angiotensin-converting enzyme inhibitor or angiotensin receptor blocker use with COVID-19 diagnosis and mortality. JAMA 2020; 324(2): 168-77.
[] [PMID: 32558877]
Mackey K, King VJ, Gurley S, et al. Risks and impact of angiotensin-converting enzyme inhibitors or angiotensin-receptor blockers on SARS-CoV-2 infection in adults. Ann Intern Med 2020; 173(3): 195-203.
[] [PMID: 32422062]
Alhenc-Gelas F, Drueke TB. Blockade of SARS-CoV-2 infection by recombinant soluble ACE2. Kidney Int 2020; 97(6): 1091-3.
[] [PMID: 32354636]
Monteil V, Kwon H, Prado P, et al. Inhibition of SARS-CoV-2 infections in engineered human tissues using clinical-grade soluble human ACE2. Cell 2020; 181(4): 905-913.e7.
[] [PMID: 32333836]
Patel AB, Verma A. Nasal ACE2 levels and COVID-19 in children. JAMA 2020; 323(23): 2386-7.
[] [PMID: 32432681]
Sanchis-Gomar F, Lavie CJ, Perez-Quilis C, Henry BM, Lippi G. Angiotensin-converting enzyme 2 and antihypertensives (angiotensin receptor blockers and angiotensin-converting enzyme inhibitors) in coronavirus disease 2019. Mayo Clin Proc 2020; 95(6): 1222-30.
[] [PMID: 32376099]
Hoffmann M, Schroeder S, Kleine-Weber H, Müller MA, Drosten C, Pöhlmann S. Nafamostat mesylate blocks activation of SARS- CoV-2: New treatment option for COVID-19. Antimicrob Agents Chemother 2020; 64(6): e00754-20.
[] [PMID: 32312781]
Han SJ, Kim HS, Kim KI, et al. Use of nafamostat mesilate as an anticoagulant during extracorporeal membrane oxygenation. J Korean Med Sci 2011; 26(7): 945-50.
[] [PMID: 21738350]
Gao Y, Li T, Han M, et al. Diagnostic utility of clinical laboratory data determinations for patients with the severe COVID-19. J Med Virol 2020; 92(7): 791-6.
[] [PMID: 32181911]
Wan S, Xiang Y, Fang W, et al. Clinical features and treatment of COVID-19 patients in northeast Chongqing. J Med Virol 2020; 92(7): 797-806.
[] [PMID: 32198776]
Kario K, Morisawa Y, Sukonthasarn A, et al. Hypertension Cardiovascular Outcome Prevention, Evidence in Asia (HOPE Asia) Network. COVID-19 and hypertension-evidence and practical management: Guidance from the HOPE Asia Network. J Clin Hypertens (Greenwich) 2020; 22(7): 1109-19.
[] [PMID: 32643874]

Rights & Permissions Print Cite
© 2024 Bentham Science Publishers | Privacy Policy