Characterization of ACE Inhibitors and AT1R Antagonists with Regard to Their Effect on ACE2 Expression and Infection with SARS-CoV-2 Using a Caco-2 Cell Model.

Marina Henke,Volker Laux,Jindrich Cinatl,Thomas Ulshöfer,Gerd Geisslinger,Philip Gribbon,Philipp Reus,Mira Grättinger,Denisa Bojkova,Ann-Kathrin Schneider,Susanne Schiffmann,Sandra Ciesek

doi:10.3390/life11080810

Abstract

Blood-pressure-lowering drugs are proposed to foster SARS-CoV-2 infection by pharmacological upregulation of angiotensin-converting enzyme 2 (ACE2), the binding partner of the virus spike (S) protein, located on the surface of the host cells. Conversely, it is postulated that angiotensin–renin system antagonists may prevent lung damage caused by SARS-CoV-2 infection, by reducing angiotensin II levels, which can induce permeability of lung endothelial barrier via its interaction with the AT1 receptor (AT1R). Methods: We have investigated the influence of the ACE inhibitors (lisinopril, captopril) and the AT1 antagonists (telmisartan, olmesartan) on the level of ACE2 mRNA and protein expression as well as their influence on the cytopathic effect of SARS-CoV-2 and on the cell barrier integrity in a Caco-2 cell model. Results: The drugs revealed no effect on ACE2 mRNA and protein expression. ACE inhibitors and AT1R antagonist olmesartan did not influence the infection rate of SARS-CoV-2 and were unable to prevent the SARS-CoV-2-induced cell barrier disturbance. A concentration of 25 µg/mL telmisartan significantly reduced the virus replication rate. Conclusion: ACE inhibitors and AT1R antagonist showed neither beneficial nor detrimental effects on SARS-CoV-2-infection and cell barrier integrity in vitro at pharmacologically relevant concentrations.

Highlights

The coronavirus disease 2019 (COVID-19) caused by the severe acute respiratory syndrome coronavirus (SARS-CoV-2) infection raises several challenges for the treatment of patients, especially for individuals with underlying illnesses such as hypertension
It is well described that SARS-CoV-2 uses angiotensin-converting enzyme 2 (ACE2) as an entry receptor [16], leading to proposals that angiotensin-converting enzyme (ACE) inhibitors and/or AT1 R antagonists may modulate the entry of SARS-CoV-2 virus via increased expression of ACE2
We observed no influence of ACE inhibitors and AT1 antagonists on SARS-CoV-2-induced infection and on SARS-CoV-2-mediated disturbance of cell barrier integrity

Summary

Introduction

The coronavirus disease 2019 (COVID-19) caused by the severe acute respiratory syndrome coronavirus (SARS-CoV-2) infection raises several challenges for the treatment of patients, especially for individuals with underlying illnesses such as hypertension. Half of COVID-19 patients develop hypotension during their hospitalization [4,5], so it is essential to clarify whether this drug group has beneficial or detrimental effects on SARS-CoV-2 infection. The angiotensin II receptor (AT) antagonists losartan, telmisartan, and olmesartan are widely used for the control of hypertension and kidney disorders and are known as relatively safe drugs [6,7]. The angiotensin-converting enzyme (ACE) blockers ramipril, captopril, and lisinopril, known for their relatively low side effects, are used worldwide for the treatment of chronic illnesses such as hypertension and diabetes [8]. ACE converts angiotensin I into angiotensin II, which mediates vasoconstriction and blood pressure-increasing effects via the AT1 -receptor. ACE2, in turn, is an aminopeptidase membrane protein, which converts angiotensin II into angiotensin 1–7 and intervenes in a regulating manner in the cardiovascular system by reducing the angiotensin

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