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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Bibliographic Details
Published in:Viruses Vol. 13; no. 11; p. 2209
Main Authors: Kumar, Nitin, Zuo, Yu, Yalavarthi, Srilakshmi, Hunker, Kristina L., Knight, Jason S., Kanthi, Yogendra, Obi, Andrea T., Ganesh, Santhi K.
Format: Journal Article
Language:English
Published: Switzerland MDPI AG 03.11.2021
MDPI
Subjects:
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
Online Access:Get full text
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Summary: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.
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ISSN:1999-4915
1999-4915
DOI:10.3390/v13112209