SARS-CoV-2 Spike Protein S1-Mediated Endothelial Injury and Pro-Inflammatory State Is Amplified by Dihydrotestosterone and Prevented by Mineralocorticoid Antagonism

Men are disproportionately affected by the coronavirus disease-2019 (COVID-19), and face higher odds of severe illness and death compared to women. The vascular effects of androgen signaling and inflammatory cytokines in severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2)-mediated endotheli...

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Autores principales:	Nitin Kumar, Yu Zuo, Srilakshmi Yalavarthi, Kristina L. Hunker, Jason S. Knight, Yogendra Kanthi, Andrea T. Obi, Santhi K. Ganesh
Formato:	article
Lenguaje:	EN
Publicado:	MDPI AG 2021
Materias:	endothelial injury androgen COVID-19 spironolactone angiotensin receptor blocker E-selectin Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/29ea2c7fc975437b97d2aac79e1dc36f
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spelling	oai:doaj.org-article:29ea2c7fc975437b97d2aac79e1dc36f2021-11-25T19:13:21ZSARS-CoV-2 Spike Protein S1-Mediated Endothelial Injury and Pro-Inflammatory State Is Amplified by Dihydrotestosterone and Prevented by Mineralocorticoid Antagonism10.3390/v131122091999-4915https://doaj.org/article/29ea2c7fc975437b97d2aac79e1dc36f2021-11-01T00:00:00Zhttps://www.mdpi.com/1999-4915/13/11/2209https://doaj.org/toc/1999-4915Men are disproportionately affected by the coronavirus disease-2019 (COVID-19), and face higher odds of severe illness and death compared to women. The vascular effects of androgen signaling and inflammatory cytokines in severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2)-mediated endothelial injury are not defined. We determined the effects of SARS-CoV-2 spike protein-mediated endothelial injury under conditions of exposure to androgen dihydrotestosterone (DHT) and tumor necrosis factor-a (TNF-α) and tested potentially therapeutic effects of mineralocorticoid receptor antagonism by spironolactone. Circulating endothelial injury markers VCAM-1 and E-selectin were measured in men and women diagnosed with COVID-19. Exposure of endothelial cells (ECs) in vitro to DHT exacerbated spike protein S1-mediated endothelial injury transcripts for the cell adhesion molecules E-selectin, VCAM-1 and ICAM-1 and anti-fibrinolytic PAI-1 (<i>p</i> < 0.05), and increased THP-1 monocyte adhesion to ECs (<i>p</i> = 0.032). Spironolactone dramatically reduced DHT+S1-induced endothelial activation. TNF-α exacerbated S1-induced EC activation, which was abrogated by pretreatment with spironolactone. Analysis from patients hospitalized with COVID-19 showed concordant higher circulating VCAM-1 and E-Selectin levels in men, compared to women. A beneficial effect of the FDA-approved drug spironolactone was observed on endothelial cells in vitro, supporting a rationale for further evaluation of mineralocorticoid antagonism as an adjunct treatment in COVID-19.Nitin KumarYu ZuoSrilakshmi YalavarthiKristina L. HunkerJason S. KnightYogendra KanthiAndrea T. ObiSanthi K. GaneshMDPI AGarticleendothelial injuryandrogenCOVID-19spironolactoneangiotensin receptor blockerE-selectinMicrobiologyQR1-502ENViruses, Vol 13, Iss 2209, p 2209 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	endothelial injury androgen COVID-19 spironolactone angiotensin receptor blocker E-selectin Microbiology QR1-502
spellingShingle	endothelial injury androgen COVID-19 spironolactone angiotensin receptor blocker E-selectin Microbiology QR1-502 Nitin Kumar Yu Zuo Srilakshmi Yalavarthi Kristina L. Hunker Jason S. Knight Yogendra Kanthi Andrea T. Obi Santhi K. Ganesh SARS-CoV-2 Spike Protein S1-Mediated Endothelial Injury and Pro-Inflammatory State Is Amplified by Dihydrotestosterone and Prevented by Mineralocorticoid Antagonism
description	Men are disproportionately affected by the coronavirus disease-2019 (COVID-19), and face higher odds of severe illness and death compared to women. The vascular effects of androgen signaling and inflammatory cytokines in severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2)-mediated endothelial injury are not defined. We determined the effects of SARS-CoV-2 spike protein-mediated endothelial injury under conditions of exposure to androgen dihydrotestosterone (DHT) and tumor necrosis factor-a (TNF-α) and tested potentially therapeutic effects of mineralocorticoid receptor antagonism by spironolactone. Circulating endothelial injury markers VCAM-1 and E-selectin were measured in men and women diagnosed with COVID-19. Exposure of endothelial cells (ECs) in vitro to DHT exacerbated spike protein S1-mediated endothelial injury transcripts for the cell adhesion molecules E-selectin, VCAM-1 and ICAM-1 and anti-fibrinolytic PAI-1 (<i>p</i> < 0.05), and increased THP-1 monocyte adhesion to ECs (<i>p</i> = 0.032). Spironolactone dramatically reduced DHT+S1-induced endothelial activation. TNF-α exacerbated S1-induced EC activation, which was abrogated by pretreatment with spironolactone. Analysis from patients hospitalized with COVID-19 showed concordant higher circulating VCAM-1 and E-Selectin levels in men, compared to women. A beneficial effect of the FDA-approved drug spironolactone was observed on endothelial cells in vitro, supporting a rationale for further evaluation of mineralocorticoid antagonism as an adjunct treatment in COVID-19.
format	article
author	Nitin Kumar Yu Zuo Srilakshmi Yalavarthi Kristina L. Hunker Jason S. Knight Yogendra Kanthi Andrea T. Obi Santhi K. Ganesh
author_facet	Nitin Kumar Yu Zuo Srilakshmi Yalavarthi Kristina L. Hunker Jason S. Knight Yogendra Kanthi Andrea T. Obi Santhi K. Ganesh
author_sort	Nitin Kumar
title	SARS-CoV-2 Spike Protein S1-Mediated Endothelial Injury and Pro-Inflammatory State Is Amplified by Dihydrotestosterone and Prevented by Mineralocorticoid Antagonism
title_short	SARS-CoV-2 Spike Protein S1-Mediated Endothelial Injury and Pro-Inflammatory State Is Amplified by Dihydrotestosterone and Prevented by Mineralocorticoid Antagonism
title_full	SARS-CoV-2 Spike Protein S1-Mediated Endothelial Injury and Pro-Inflammatory State Is Amplified by Dihydrotestosterone and Prevented by Mineralocorticoid Antagonism
title_fullStr	SARS-CoV-2 Spike Protein S1-Mediated Endothelial Injury and Pro-Inflammatory State Is Amplified by Dihydrotestosterone and Prevented by Mineralocorticoid Antagonism
title_full_unstemmed	SARS-CoV-2 Spike Protein S1-Mediated Endothelial Injury and Pro-Inflammatory State Is Amplified by Dihydrotestosterone and Prevented by Mineralocorticoid Antagonism
title_sort	sars-cov-2 spike protein s1-mediated endothelial injury and pro-inflammatory state is amplified by dihydrotestosterone and prevented by mineralocorticoid antagonism
publisher	MDPI AG
publishDate	2021
url	https://doaj.org/article/29ea2c7fc975437b97d2aac79e1dc36f
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SARS-CoV-2 Spike Protein S1-Mediated Endothelial Injury and Pro-Inflammatory State Is Amplified by Dihydrotestosterone and Prevented by Mineralocorticoid Antagonism

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