No evidence that RAS blockers facilitate SARS-CoV-2 entry into cells
Renin-Angiotensin System Blockers and the COVID-19 Pandemic
Literature - Danser AHJ, Epstein M and Batlle D - Hypertension 2020, doi: 10.1161/HYPERTENSIONAHA.120.15082.The commentary article by Danser et al. in Hypertension provides an in-dept description of the properties and function of ACE2, the receptor responsible for SARS-CoV-2 entry into cells. Furthermore, the authors describe the currently available scientific evidence on the effects of RAS blockers on ACE2 and motivate why RAS blockers should not be discontinued because of concerns related to coronavirus infection.
ACE inhibitors do not inhibit ACE2
Angiotensin-converting enzyme 2 (ACE2) is the receptor responsible for entry of SARS-CoV-2, the virus causing COVID-19, into cells [1,2]. A surface unit of a viral spike protein is required for binding to ACE2 and priming by the serine protease TMPRSS2 is needed for subsequent cell entry [3,4 ].
ACE2 converts angiotensin II (Ang II) to Ang-(1-7) and Ang I to Ang-(1-9) [5,6]. ACE2 and ACE are two different enzymes with 2 different active sites. ACE inhibitors prevent the conversion of Ang I to Ang II by ACE, but ACE inhibitors do not inhibit ACE2.
ACE2 is a membrane-bound enzyme [7,8]. The membrane-anchor can be cleaved by a disintegrin and metalloprotease 17 (ADAM17). The shorter (soluble) form of ACE2 can subsequently be found in body fluids, albeit at very low levels [7,8]. SARS-CoV-2 entry depends on membrane-bound ACE2. Shedding of ACE2 is often increased in pathological states, resulting in elevated levels of ACE2 in body fluids [9,10]. A doubling of soluble ACE2 has for instance been reported in patients with hypertension [11]. However, the fast majority of ACE2 is membrane-bound and it is therefore unlikely that a doubling of soluble ACE2 can significantly alter the amount of membrane-bound ACE2. In theory, RAS blockage could (partly) reverse this increase in shedding. However, it is unlikely that this will seriously affect SARS-CoV-2 entry.
Effects of RAS blockers on ACE2
Since ACE inhibitors do not inhibit ACE2, any effect of ACE inhibitors on ACE2 activity must be of indirect nature. There are limited reports from animal studies that ACE inhibitors affect the expression of ACE2 in the heart and kidney [12]. Some animal studies showed that AT1 receptor blockers (ARBs) alter ACE2 expression at the mRNA and protein level. However, high doses were required, and results differed per ARB and per organ [12-14].
Measuring membrane-bound ACE2 in vivo is technically challenging. Most publications in humans have therefore reported levels of ACE2 activity in blood, reflecting soluble ACE2 circulating at very low levels [15]. Even if upregulation of tissue ACE2 by ARBs at high doses as reported in animal studies could be extrapolated to humans, this would not provide evidence that increased ACE2 expression is sufficient to facilitate SARS-CoV-2 entry into cells.
The authors also address a potentially beneficial pulmonary effect of ARBs. Alveolar ACE2 appears to be downregulated during acute lung injury [16,17]. This would result in lower Ang II metabolism and consequently higher local Ang II levels, which increases alveolar permeability and fosters lung injury. The authors speculate that, in this context, increased ACE2 expression by ARBs could potentially have protective effects during a SARS-CoV-2 infection.
RAS blockers should not be discontinued due to coronavirus concerns
A notion has been popularized via social media and in the general public that treatment with RAS blockers might increase the risk of SARS-CoV-2 infection and severity of infection. However, as explained in this article there is no evidence that ACE inhibitors or ARBs facilitate SARS-CoV-2 entry by increasing ACE2 expression in either animals or humans. The authors therefore strongly recommend that patients who are taking ACE inhibitors or ARBs should not withdraw their current treatment unless specifically advised to do so by their physician or healthcare provider. The therapeutic benefit outweighs any potential risk related to a coronavirus infection, according to the authors. The advice on continued use of RAS blockers is in line with position statements released by the ESC and HFSA/ACC/AHA .
A prospective cohort study with incidence rates of SARS-CoV-2 infection in patients with and without hypertension, with similar exposure history, is required to investigate whether hypertensive patients are more likely to get serious and fatal SARS-CoV-2 infections.
References
1. Hoffmann M, Kleine-Weber H, Schroeder S, Kruger N, Herrler T, Erichsen S, Schiergens TS, Herrler G, Wu NH, Nitsche A, et al. SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor. Cell. 2020;in press. doi:10.1016/j.cell.2020.02.052
2. Zhou P, Yang XL, Wang XG, Hu B, Zhang L, Zhang W, Si HR, Zhu Y, Li B, Huang CL, et al. A pneumonia outbreak associated with a new coronavirus of probable bat origin. Nature. 2020;579:270–273. doi:10.1038/s41586-020-2012-7
3. Matsuyama S, Nagata N, Shirato K, Kawase M, Takeda M, Taguchi F. Efficient activation of the severe acute respiratory syndrome coronavirus spike protein by the transmembrane protease TMPRSS2. J Virol. 2010;84:12658–12664. doi: 10.1128/JVI.01542-10
4. Batlle D, Wysocki J, Satchell K. Soluble angiotensin-converting enzyme 2: a potential approach for coronavirus infection therapy? Clin Sci (Lond). 2020;134:543–545. doi: 10.1042/CS20200163
5. Batlle D, Wysocki J, Soler MJ, Ranganath K. Angiotensin-converting enzyme 2: enhancing the degradation of angiotensin II as a potential therapy for diabetic nephropathy. Kidney Int. 2012;81:520–528. doi: 10.1038/ki.2011.381
6. Ferrario CM, Chappell MC, Tallant EA, Brosnihan KB, Diz DI. Counterregulatory actions of angiotensin-(1-7). Hypertension. 1997;30(3 Pt 2):535–541. doi: 10.1161/01.hyp.30.3.535
7. Serfozo P, Wysocki J, Gulua G, Schulze A, Ye M, Liu P, Jin J, Bader M, Myöhänen T, García-Horsman JA, 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;75:173–182. doi: 10.1161/HYPERTENSIONAHA.119.14071
8. Arendse LB, Danser AHJ, Poglitsch M, Touyz RM, Burnett JC Jr, Llorens-Cortes C, Ehlers MR, Sturrock ED. Novel therapeutic approaches targeting the renin-angiotensin system and associated peptides in hypertension and heart failure. Pharmacol Rev. 2019;71:539–570. doi: 10.1124/pr.118.017129
9. Wysocki J, Goodling A, Burgaya M, Whitlock K, Ruzinski J, Batlle D, Afkarian M. Urine RAS components in mice and people with type 1 diabetes and chronic kidney disease. Am J Physiol Renal Physiol. 2017;313:F487–F494. doi: 10.1152/ajprenal.00074.2017
10. Bitker L, Burrell LM. Classic and nonclassic renin-angiotensin systems in the critically ill. Crit Care Clin. 2019;35:213–227. doi: 10.1016/j.ccc.2018.11.002
11. Xu J, Sriramula S, Xia H, Moreno-Walton L, Culicchia F, Domenig O, Poglitsch M, Lazartigues E. Clinical relevance and role of neuronal AT1 receptors in ADAM17-mediated ACE2 shedding in neurogenic hypertension. Circ Res. 2017;121:43–55. doi: 10.1161/CIRCRESAHA.116.310509
12. Ferrario CM, Jessup J, Chappell MC, Averill DB, Brosnihan KB, Tallant EA, Diz DI, Gallagher PE. Effect of angiotensin-converting enzyme inhibition and angiotensin II receptor blockers on cardiac angiotensin-converting enzyme 2. Circulation. 2005;111:2605–2610. doi: 10.1161/CIRCULATIONAHA.104.510461
13. Wang X, Ye Y, Gong H, Wu J, Yuan J, Wang S, Yin P, Ding Z, Kang L, Jiang Q, et al. 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;97:180–190. doi: 10.1016/j.yjmcc.2016.05.012
14. Soler MJ, Ye M, Wysocki J, William J, Lloveras J, Batlle D. Localization of ACE2 in the renal vasculature: amplification by angiotensin II type 1 receptor blockade using telmisartan. Am J Physiol Renal Physiol. 2009;296:F398–F405. doi: 10.1152/ajprenal.90488.2008
15. Ramchand J, Patel SK, Kearney LG, Matalanis G, Farouque O, Srivastava PM, Burrell LM. Plasma ACE2 activity predicts mortality in aortic stenosis and is associated with severe myocardial fibrosis. JACC Cardiovasc Imaging. 2020;13:655–664. doi: 10.1016/j. jcmg.2019.09.005
Facebook Comments