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Abstract
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.
Highlights
Utilizing molecular and functional assays, we demonstrated that SARS-CoV-2 S1 exacerbated endothelial injury in the presence of DHT and tumor necrosis factor-α (TNF-α) in vitro, and this was abrogated by the mineralocorticoid receptor antagonist spironolactone
We investigated the effect of exposure to the S1 subunit of SARS-CoV-2 (S1) on endothelial injury in vitro by screening quantitative transcript expression levels of cell surface adhesion proteins [E-selectin, vascular cell adhesion molecule-1 (VCAM-1) and intercellular adhesion molecule-1 (ICAM-1)] and anti-fibrinolytic/fibrinolytic markers
Further validation in human samples from patients hospitalized to the cultured endothelial cells (ECs), which was shown to be increased in the setting of S1 exposure of the with COVID-19 infection showed that circulating endothelial injury markers VCAM-1 and
Summary
Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) is a new and rapidly mutating virus causing the COVID-19 pandemic, affecting millions of people globally. SARS-CoV-2 invades human cells by utilizing angiotensin-converting enzyme 2 (ACE2) as a cognate receptor, after being primed by transmembrane protease serine 2 (TMPRSS2), an androgen regulated gene [1,2]. SARS-CoV2 infection is attenuated by anti-ACE2 antibodies, while SARS-CoV infection is enhanced in mice overexpressing ACE2 [3,4]. TMPRSS2 knockout mice show reduced SARS-CoV replication and milder lung damage, implying critical roles of ACE2 and TMPRSS2 in SARS coronavirus infection [5,6]
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