Journal
VIRUSES-BASEL
Volume 13, Issue 11, Pages -Publisher
MDPI
DOI: 10.3390/v13112209
Keywords
endothelial injury; androgen; COVID-19; spironolactone; angiotensin receptor blocker; E-selectin
Categories
Funding
- University of Michigan Frankel Cardiovascular Center Michigan Biological Research Initiative on Sex Differences in Cardiovascular Disease (M-BRISC)
- Department of Defense [R01HL139672, R01HL122684, R01HL086694]
- University of Michigan A. Alfred Taubman Institute
- National Center for Advancing Translational Sciences, NIH [UL1TR002240]
- Rheumatology Research Foundation
- Michigan Medicine Frankel Cardiovascular Center
- A. Alfred Taubman Medical Research Institute
- Arthritis National Research Foundation
- NIH [R01HL115138]
- Burroughs Wellcome Fund
- Lupus Research Alliance
- Intramural Research Program of the NIH
- NHLBI [ZIAHL006262, ZIAHL006263]
- Lasker Foundation
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Men are more severely affected by COVID-19 compared to women, potentially due to the effects of androgen signaling and inflammatory cytokines in SARS-CoV-2-induced endothelial injury. The drug spironolactone demonstrated a protective effect on endothelial cells in vitro, suggesting it may be a potential adjunct treatment for COVID-19.
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-alpha) 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-alpha 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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