Effect of Angiotensin-Converting-Enzyme Inhibitor and Angiotensin II Receptor Antagonist Treatment on ACE2 Expression and SARS-CoV-2 Replication in Primary Airway Epithelial Cells

Rationale: SARS-CoV-2 gains entrance to airway epithelial cells (AECs) through binding of the viral spike protein to the angiotensin-converting enzyme 2 (ACE2) on the cell surface. However, ACE2 also converts angiotensin II into angiotensin-(1-7) and counterbalances the renin-angiotensin-aldosterone...

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Autores principales:	Oghenemega Okoloko, Elizabeth R. Vanderwall, Lucille M. Rich, Maria P. White, Stephen R. Reeves, Whitney E. Harrington, Kaitlyn A. Barrow, Jason S. Debley
Formato:	article
Lenguaje:	EN
Publicado:	Frontiers Media S.A. 2021
Materias:	airway epithelium SARS—CoV—2 ACE2 angiotensin-converting eitzyme inhibitors angiotensin II (A II) receptor antagonists Therapeutics. Pharmacology RM1-950
Acceso en línea:	https://doaj.org/article/26e83c257499441486daeccf5e446cf8
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spelling	oai:doaj.org-article:26e83c257499441486daeccf5e446cf82021-11-19T07:51:02ZEffect of Angiotensin-Converting-Enzyme Inhibitor and Angiotensin II Receptor Antagonist Treatment on ACE2 Expression and SARS-CoV-2 Replication in Primary Airway Epithelial Cells1663-981210.3389/fphar.2021.765951https://doaj.org/article/26e83c257499441486daeccf5e446cf82021-11-01T00:00:00Zhttps://www.frontiersin.org/articles/10.3389/fphar.2021.765951/fullhttps://doaj.org/toc/1663-9812Rationale: SARS-CoV-2 gains entrance to airway epithelial cells (AECs) through binding of the viral spike protein to the angiotensin-converting enzyme 2 (ACE2) on the cell surface. However, ACE2 also converts angiotensin II into angiotensin-(1-7) and counterbalances the renin-angiotensin-aldosterone system, with resultant protective effects in the cardiovascular system. Some data suggest that two common antihypertension medications (angiotensin II receptor antagonists, ARBs; and angiotensin-converting-enzyme inhibitors, ACEIs) may increase ACE2 expression in heart and kidney cells, fueling debate about how these widely used medications may modulate SARS-CoV-2 infectivity and risk of COVID-19.Aim: Determine whether exposure of bronchial AECs to the ARB losartan or the ACEI captopril modulate expression of ACE2 by AECs, SARS CoV2 replication, or expression of proinflammatory cytokines and type I and III interferon (IFN) responses.Methods: Primary bronchial AECs from children and adults (n = 19; Ages 8–75 yrs) were differentiated ex vivo at an air-liquid interface to generate organotypic cultures. Cultures were treated with captopril (1 μM) or losartan (2 μM) with culture media changes starting 72 h before infection with SARS-CoV-2. In a biosafety level 3 (BSL-3) facility, cultures were infected with SARS-CoV-2 isolate USA-WA1/2020 at a multiplicity of infection (MOI) of 0.5. At 96 h following infection, RNA and protein were isolated. SARS-CoV-2 replication in cultures was assessed with quantitative PCR (qPCR). ACE2, IL-6, IL-1B, IFNB1, and IFNL2 expression were assessed by qPCR.Results: Neither captopril nor losartan treatment significantly changed ACE2, IL-6, IL-1B, IFNB1, or IFNL2 expression by AECs as compared to SARS-CoV-2 infected AEC cultures without captopril or losartan treatment. At 96 h following infection, SARS-CoV-2 copy number/ng RNA was not significantly different between untreated AEC cultures, cultures treated with captopril, or cultures treated with losartan.Conclusion: These findings suggest that at the level of the airway epithelium neither the ACEI captopril or ARB losartan significantly modify expression of the SARS-CoV-2 entry factor ACE2, nor does either medication increase replication SARS-CoV-2 replication. This ex vivo data is reassuring and is consistent with evolving clinical data suggesting ACEIs and ARBs do not increase the risk for poor prognosis with COVID-19 and may actually reduce the risk of COVID-19 disease.Oghenemega OkolokoElizabeth R. VanderwallLucille M. RichMaria P. WhiteStephen R. ReevesStephen R. ReevesWhitney E. HarringtonWhitney E. HarringtonKaitlyn A. BarrowJason S. DebleyJason S. DebleyFrontiers Media S.A.articleairwayepitheliumSARS—CoV—2ACE2angiotensin-converting eitzyme inhibitorsangiotensin II (A II) receptor antagonistsTherapeutics. PharmacologyRM1-950ENFrontiers in Pharmacology, Vol 12 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	airway epithelium SARS—CoV—2 ACE2 angiotensin-converting eitzyme inhibitors angiotensin II (A II) receptor antagonists Therapeutics. Pharmacology RM1-950
spellingShingle	airway epithelium SARS—CoV—2 ACE2 angiotensin-converting eitzyme inhibitors angiotensin II (A II) receptor antagonists Therapeutics. Pharmacology RM1-950 Oghenemega Okoloko Elizabeth R. Vanderwall Lucille M. Rich Maria P. White Stephen R. Reeves Stephen R. Reeves Whitney E. Harrington Whitney E. Harrington Kaitlyn A. Barrow Jason S. Debley Jason S. Debley Effect of Angiotensin-Converting-Enzyme Inhibitor and Angiotensin II Receptor Antagonist Treatment on ACE2 Expression and SARS-CoV-2 Replication in Primary Airway Epithelial Cells
description	Rationale: SARS-CoV-2 gains entrance to airway epithelial cells (AECs) through binding of the viral spike protein to the angiotensin-converting enzyme 2 (ACE2) on the cell surface. However, ACE2 also converts angiotensin II into angiotensin-(1-7) and counterbalances the renin-angiotensin-aldosterone system, with resultant protective effects in the cardiovascular system. Some data suggest that two common antihypertension medications (angiotensin II receptor antagonists, ARBs; and angiotensin-converting-enzyme inhibitors, ACEIs) may increase ACE2 expression in heart and kidney cells, fueling debate about how these widely used medications may modulate SARS-CoV-2 infectivity and risk of COVID-19.Aim: Determine whether exposure of bronchial AECs to the ARB losartan or the ACEI captopril modulate expression of ACE2 by AECs, SARS CoV2 replication, or expression of proinflammatory cytokines and type I and III interferon (IFN) responses.Methods: Primary bronchial AECs from children and adults (n = 19; Ages 8–75 yrs) were differentiated ex vivo at an air-liquid interface to generate organotypic cultures. Cultures were treated with captopril (1 μM) or losartan (2 μM) with culture media changes starting 72 h before infection with SARS-CoV-2. In a biosafety level 3 (BSL-3) facility, cultures were infected with SARS-CoV-2 isolate USA-WA1/2020 at a multiplicity of infection (MOI) of 0.5. At 96 h following infection, RNA and protein were isolated. SARS-CoV-2 replication in cultures was assessed with quantitative PCR (qPCR). ACE2, IL-6, IL-1B, IFNB1, and IFNL2 expression were assessed by qPCR.Results: Neither captopril nor losartan treatment significantly changed ACE2, IL-6, IL-1B, IFNB1, or IFNL2 expression by AECs as compared to SARS-CoV-2 infected AEC cultures without captopril or losartan treatment. At 96 h following infection, SARS-CoV-2 copy number/ng RNA was not significantly different between untreated AEC cultures, cultures treated with captopril, or cultures treated with losartan.Conclusion: These findings suggest that at the level of the airway epithelium neither the ACEI captopril or ARB losartan significantly modify expression of the SARS-CoV-2 entry factor ACE2, nor does either medication increase replication SARS-CoV-2 replication. This ex vivo data is reassuring and is consistent with evolving clinical data suggesting ACEIs and ARBs do not increase the risk for poor prognosis with COVID-19 and may actually reduce the risk of COVID-19 disease.
format	article
author	Oghenemega Okoloko Elizabeth R. Vanderwall Lucille M. Rich Maria P. White Stephen R. Reeves Stephen R. Reeves Whitney E. Harrington Whitney E. Harrington Kaitlyn A. Barrow Jason S. Debley Jason S. Debley
author_facet	Oghenemega Okoloko Elizabeth R. Vanderwall Lucille M. Rich Maria P. White Stephen R. Reeves Stephen R. Reeves Whitney E. Harrington Whitney E. Harrington Kaitlyn A. Barrow Jason S. Debley Jason S. Debley
author_sort	Oghenemega Okoloko
title	Effect of Angiotensin-Converting-Enzyme Inhibitor and Angiotensin II Receptor Antagonist Treatment on ACE2 Expression and SARS-CoV-2 Replication in Primary Airway Epithelial Cells
title_short	Effect of Angiotensin-Converting-Enzyme Inhibitor and Angiotensin II Receptor Antagonist Treatment on ACE2 Expression and SARS-CoV-2 Replication in Primary Airway Epithelial Cells
title_full	Effect of Angiotensin-Converting-Enzyme Inhibitor and Angiotensin II Receptor Antagonist Treatment on ACE2 Expression and SARS-CoV-2 Replication in Primary Airway Epithelial Cells
title_fullStr	Effect of Angiotensin-Converting-Enzyme Inhibitor and Angiotensin II Receptor Antagonist Treatment on ACE2 Expression and SARS-CoV-2 Replication in Primary Airway Epithelial Cells
title_full_unstemmed	Effect of Angiotensin-Converting-Enzyme Inhibitor and Angiotensin II Receptor Antagonist Treatment on ACE2 Expression and SARS-CoV-2 Replication in Primary Airway Epithelial Cells
title_sort	effect of angiotensin-converting-enzyme inhibitor and angiotensin ii receptor antagonist treatment on ace2 expression and sars-cov-2 replication in primary airway epithelial cells
publisher	Frontiers Media S.A.
publishDate	2021
url	https://doaj.org/article/26e83c257499441486daeccf5e446cf8
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Effect of Angiotensin-Converting-Enzyme Inhibitor and Angiotensin II Receptor Antagonist Treatment on ACE2 Expression and SARS-CoV-2 Replication in Primary Airway Epithelial Cells

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