In the Comment article by Zheng and colleagues (COVID-19 and the cardiovascular system. Nat. Rev. Cardiol. https://doi.org/10.1038/s41569-020-0360-5 (2020))1, the crucial role of angiotensin-converting enzyme 2 (ACE2) in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, which causes coronavirus disease 2019 (COVID-19), was highlighted. ACE2 is a membrane-bound aminopeptidase that cleaves angiotensin I and angiotensin II into the angiotensin-(1–9) and angiotensin-(1–7) peptides. Several studies support the existence of a cardiovascular-protective ACE2–angiotensin-(1–7)–Mas receptor axis2. ACE2 is overexpressed in heart failure, arterial hypertension and diabetes mellitus3. Moreover, ACE2 has been identified as a functional receptor for the entry of coronaviruses generally, and SARS-CoV-2 specifically, into host cells4.
Given that most of the severe forms of COVID-19 have occurred in elderly patients with cardiovascular comorbidities, Zheng and colleagues speculate about the influence of chronic treatment with blockers of the renin–angiotensin–aldosterone system (RAAS) on the severity of the infection, stating that “ACE2 levels can be increased by the use of renin–angiotensin–aldosterone system inhibitors”1. Consequently, the authors suggest that “the safety and potential effects of antihypertension therapy with ACE inhibitors or angiotensin-receptor blockers in patients with COVID-19 should be carefully considered”.
We wish to clarify that different RAAS inhibitors have different effects on ACE2 levels. By acting at different levels of the system, RAAS inhibitors result in heterogeneous effects on the peptides and enzymes involved. Whereas angiotensin-receptor blockers and mineralocorticoid-receptor blockers have been shown to increase the levels of ACE2 expression and activity in various experimental and clinical models5,6, administration of ACE inhibitors increased cardiac Ace2 mRNA levels but had no effect on ACE2 activity in experimental models7,8. In addition, in an animal model of diabetic nephropathy, the chronic administration of aliskiren (a direct inhibitor of renin) was associated with a reduction in ACE2 expression9. For these reasons, we believe that chronic treatment with ACE inhibitors has no reason to influence the course of SARS-CoV-2 infection. By contrast, the use of angiotensin-receptor blockers or mineralocorticoid-receptor blockers might warrant caution and further analysis in the context of SARS-CoV-2 infection. The reduced expression of ACE2 with aliskiren treatment could be an interesting option in the context of SARS-CoV-2 infection that requires further investigation.
There is a reply to this letter by Zheng, Y. Y. et al. Nat. Rev. Cardiol. https://doi.org/10.1038/s41569-020-0369-9 (2020).
Zheng, Y. Y., Ma, Y. T., Zhang, J. Y. & Xie, X. COVID-19 and the cardiovascular system. Nat. Rev. Cardiol. https://doi.org/10.1038/s41569-020-0360-5 (2020).
Patel, V. B., Zhong, J. C., Grant, M. B. & Oudit, G. Y. Role of the ACE2/angiotensin 1–7 axis of the renin–angiotensin system in heart failure. Circ. Res. 118, 1313–1326 (2016).
Te Riet, L., van Esch, J. H., Roks, A. J., van den Meiracker, A. H. & Danser, A. H. Hypertension: renin–angiotensin–aldosterone system alterations. Circ. Res. 116, 960–975 (2015).
Hoffmann, M. et al. SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor. Cell https://doi.org/10.1016/j.cell.2020.02.052 (2020).
Keidar, S. et al. Mineralocorticoid receptor blocker increases angiotensin-converting enzyme 2 activity in congestive heart failure patients. Circ. Res. 97, 946–953 (2005).
Zhong, J. C. et al. Telmisartan attenuates aortic hypertrophy in hypertensive rats by the modulation of ACE2 and profilin-1 expression. Regul. Pept. 166, 90–97 (2011).
Ferrario, C. M. et al. Effect of angiotensin-converting enzyme inhibition and angiotensin II receptor blockers on cardiac angiotensin-converting enzyme 2. Circulation 111, 2605–2610 (2005).
Tipnis, S. R. et al. A human homolog of angiotensin-converting enzyme: cloning and functional expression as a captopril-insensitive carboxypeptidase. J. Biol. Chem. 275, 33238–33243 (2000).
Ding, W. et al. Aliskiren inhibits angiotensin II/angiotensin 1–7 (Ang II/Ang1–7) signal pathway in rats with diabetic nephropathy [Chinese]. Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi 34, 891–895 (2018).
J.-J.M. has received fees for consultancy from Mylan, Pfizer and Servier. B.I.L. has received grants and personal fees from Bayer, Roche and Servier.
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Mourad, JJ., Levy, B.I. Interaction between RAAS inhibitors and ACE2 in the context of COVID-19. Nat Rev Cardiol 17, 313 (2020). https://doi.org/10.1038/s41569-020-0368-x
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