Effects of Angiotensin-Converting Enzyme Inhibitors and Angiotensin Receptor Blockers on Angiotensin-Converting Enzyme 2 Levels: A Comprehensive Analysis Based on Animal Studies

Overview

Journal Front Pharmacol

Date 2021 Mar 25

PMID 33762942

Citations 18

Authors

Gabor Kriszta

Zsofia Kriszta

Szilard Vancsa

Peter Jeno Hegyi

Levente Frim

Balint Eross

Peter Hegyi

Gabor Petho

Erika Pinter

Affiliations

Soon will be listed here.

Abstract

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the pathogen of coronavirus disease 2019 (COVID-19), caused the outbreak escalated to pandemic. Reports suggested that near 1-3% of COVID-19 cases have a fatal outcome. Angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) are widely used in hypertension, heart failure and chronic kidney disease. These drugs have been reported to upregulate angiotensin converting enzyme 2 (ACE2) which produces Ang (1-7), the main counter-regulatory mediator of angiotensin II. This enzyme is also known as the receptor of SARS-CoV-2 promoting the cellular uptake of the virus in the airways, however, ACE2 itself proved to be protective in several experimental models of lung injury. The present study aimed to systematically review the relationship between ACEI/ARB administration and ACE2 expression in experimental models. After a comprehensive search and selection, 27 animal studies investigating ACE2 expression in the context of ACEI and ARB were identified. The majority of these papers reported increased ACE2 levels in response to ACEI/ARB treatment. This result should be interpreted in the light of the dual role of ACE2 being a promoter of viral entry to cells and a protective factor against oxidative damage in the lungs.

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References

Wang X, Ye Y, Gong H, Wu J, Yuan J, Wang S . The effects of different angiotensin II type 1 receptor blockers on the regulation of the ACE-AngII-AT1 and ACE2-Ang(1-7)-Mas axes in pressure overload-induced cardiac remodeling in male mice. J Mol Cell Cardiol. 2016; 97:180-90. DOI: 10.1016/j.yjmcc.2016.05.012. View

Agata J, Ura N, Yoshida H, Shinshi Y, Sasaki H, Hyakkoku M . Olmesartan is an angiotensin II receptor blocker with an inhibitory effect on angiotensin-converting enzyme. Hypertens Res. 2007; 29(11):865-74. DOI: 10.1291/hypres.29.865. View

Jessup J, Gallagher P, Averill D, Brosnihan K, Tallant E, Chappell M . Effect of angiotensin II blockade on a new congenic model of hypertension derived from transgenic Ren-2 rats. Am J Physiol Heart Circ Physiol. 2006; 291(5):H2166-72. DOI: 10.1152/ajpheart.00061.2006. View

Dusing R . Pharmacological interventions into the renin-angiotensin system with ACE inhibitors and angiotensin II receptor antagonists: effects beyond blood pressure lowering. Ther Adv Cardiovasc Dis. 2016; 10(3):151-61. PMC: 5933673. DOI: 10.1177/1753944716644130. View

Husain K, Hernandez W, Ansari R, Ferder L . Inflammation, oxidative stress and renin angiotensin system in atherosclerosis. World J Biol Chem. 2015; 6(3):209-17. PMC: 4549761. DOI: 10.4331/wjbc.v6.i3.209. View

Zhou P, Yang X, Wang X, Hu B, Zhang L, Zhang W . A pneumonia outbreak associated with a new coronavirus of probable bat origin. Nature. 2020; 579(7798):270-273. PMC: 7095418. DOI: 10.1038/s41586-020-2012-7. View

Sampaio W, de Castro C, Santos R, Schiffrin E, Touyz R . Angiotensin-(1-7) counterregulates angiotensin II signaling in human endothelial cells. Hypertension. 2007; 50(6):1093-8. DOI: 10.1161/HYPERTENSIONAHA.106.084848. View

Burrell L, Risvanis J, Kubota E, Dean R, Macdonald P, Lu S . Myocardial infarction increases ACE2 expression in rat and humans. Eur Heart J. 2005; 26(4):369-75. DOI: 10.1093/eurheartj/ehi114. View

Zou Z, Yan Y, Shu Y, Gao R, Sun Y, Li X . Angiotensin-converting enzyme 2 protects from lethal avian influenza A H5N1 infections. Nat Commun. 2014; 5:3594. PMC: 7091848. DOI: 10.1038/ncomms4594. View

10.

Liu X, Long C, Xiong Q, Chen C, Ma J, Su Y . Association of angiotensin converting enzyme inhibitors and angiotensin II receptor blockers with risk of COVID-19, inflammation level, severity, and death in patients with COVID-19: A rapid systematic review and meta-analysis. Clin Cardiol. 2020; . PMC: 7436520. DOI: 10.1002/clc.23421. View

11.

Kuba K, Imai Y, Ohto-Nakanishi T, Penninger J . 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. PMC: 7112678. DOI: 10.1016/j.pharmthera.2010.06.003. View

12.

Azevedo P, Polegato B, Minicucci M, Paiva S, Zornoff L . Cardiac Remodeling: Concepts, Clinical Impact, Pathophysiological Mechanisms and Pharmacologic Treatment. Arq Bras Cardiol. 2015; 106(1):62-9. PMC: 4728597. DOI: 10.5935/abc.20160005. View

13.

Diaz J . Hypothesis: angiotensin-converting enzyme inhibitors and angiotensin receptor blockers may increase the risk of severe COVID-19. J Travel Med. 2020; 27(3). PMC: 7184445. DOI: 10.1093/jtm/taaa041. View

14.

Lautner R, Villela D, Fraga-Silva R, Silva N, Verano-Braga T, Costa-Fraga F . Discovery and characterization of alamandine: a novel component of the renin-angiotensin system. Circ Res. 2013; 112(8):1104-11. DOI: 10.1161/CIRCRESAHA.113.301077. View

15.

Takeda Y, Zhu A, Yoneda T, Usukura M, Takata H, Yamagishi M . Effects of aldosterone and angiotensin II receptor blockade on cardiac angiotensinogen and angiotensin-converting enzyme 2 expression in Dahl salt-sensitive hypertensive rats. Am J Hypertens. 2007; 20(10):1119-24. DOI: 10.1016/j.amjhyper.2007.05.008. View

16.

Whaley-Connell A, Chowdhury N, Hayden M, Stump C, Habibi J, Wiedmeyer C . Oxidative stress and glomerular filtration barrier injury: role of the renin-angiotensin system in the Ren2 transgenic rat. Am J Physiol Renal Physiol. 2006; 291(6):F1308-14. DOI: 10.1152/ajprenal.00167.2006. View

17.

Davis J, Freeman R . Mechanisms regulating renin release. Physiol Rev. 1976; 56(1):1-56. DOI: 10.1152/physrev.1976.56.1.1. View

18.

Inoue Y, Tanaka N, Tanaka Y, Inoue S, Morita K, Zhuang M . Clathrin-dependent entry of severe acute respiratory syndrome coronavirus into target cells expressing ACE2 with the cytoplasmic tail deleted. J Virol. 2007; 81(16):8722-9. PMC: 1951348. DOI: 10.1128/JVI.00253-07. View

19.

Li Y, Cao Y, Zeng Z, Liang M, Xue Y, Xi C . Angiotensin-converting enzyme 2/angiotensin-(1-7)/Mas axis prevents lipopolysaccharide-induced apoptosis of pulmonary microvascular endothelial cells by inhibiting JNK/NF-κB pathways. Sci Rep. 2015; 5:8209. PMC: 4314638. DOI: 10.1038/srep08209. View

20.

Kreutz R, Algharably E, Azizi M, Dobrowolski P, Guzik T, Januszewicz A . Hypertension, the renin-angiotensin system, and the risk of lower respiratory tract infections and lung injury: implications for COVID-19. Cardiovasc Res. 2020; 116(10):1688-1699. PMC: 7184480. DOI: 10.1093/cvr/cvaa097. View