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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Vydané v:	Viruses Ročník 13; číslo 11; s. 2209
Hlavní autori:	Kumar, Nitin, Zuo, Yu, Yalavarthi, Srilakshmi, Hunker, Kristina L., Knight, Jason S., Kanthi, Yogendra, Obi, Andrea T., Ganesh, Santhi K.
Médium:	Journal Article
Jazyk:	English
Vydavateľské údaje:	Switzerland MDPI AG 03.11.2021 MDPI
Predmet:	adhesion androgen Androgens Angiotensin Receptor Antagonists - pharmacology angiotensin receptor blocker antagonism cell adhesion Cell adhesion & migration Cell adhesion molecules Cell Adhesion Molecules - blood Cells, Cultured Coronaviruses COVID-19 COVID-19 - pathology COVID-19 - physiopathology COVID-19 - virology COVID-19 infection death Dihydrotestosterone Dihydrotestosterone - pharmacology disease severity Disease transmission E-selectin Endothelial cells endothelial injury Endothelium Endothelium, Vascular - drug effects Endothelium, Vascular - metabolism Endothelium, Vascular - pathology Female Fibrin Gender differences Heart failure Humans Infections Inflammation Intercellular adhesion molecule 1 Male mineralocorticoid receptors Monocytes Pandemics Proteins SARS-CoV-2 - physiology Severe acute respiratory syndrome coronavirus 2 Sex Characteristics Spike Glycoprotein, Coronavirus - physiology Spike protein spironolactone Spironolactone - pharmacology therapeutics tumor necrosis factor-alpha Tumor Necrosis Factor-alpha - pharmacology Tumor Necrosis Factor-alpha - physiology Tumor necrosis factor-TNF Tumor necrosis factor-α Valsartan - pharmacology Vascular cell adhesion molecule 1 vascular cell adhesion molecules Viral infections Women St Louis Missouri United States > US COVID-19 E-selectin androgen angiotensin receptor blocker spironolactone endothelial injury
ISSN:	1999-4915, 1999-4915
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Shrnutí:	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 (p < 0.05), and increased THP-1 monocyte adhesion to ECs (p = 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.
Bibliografia:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 content type line 23
ISSN:	1999-4915 1999-4915
DOI:	10.3390/v13112209