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

Background: Men are disproportionately affected by the coronavirus disease-2019 (COVID-19) and experience higher mortality as compared to women. The vascular effects of androgen signaling and inflammatory cytokines in severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2)-mediated endothelial damage are not defined.Methods: Here, we determined the effects of SARS-CoV-2 spike protein-mediated endothelial damage under conditions of exposure to androgens and TNF-α. We tested the therapeutic effects of approved drugs: angiotensin receptor blockade by valsartan and mineralocorticoid receptor antagonism by spironolactone. Circulating endothelial injury markers VCAM-1 and E-selectin were measured in the plasma from men and women diagnosed with COVID-19.Findings: Exposure of endothelial cells (ECs) in vitro to androgen dihydrotestosterone (DHT) exacerbated spike protein S1-mediated endothelial injury transcripts for cell adhesion molecules E-selectin, VCAM-1, and ICAM-1 and anti-fibrinolytic PAI-1 (P<0.05), as well as increased THP-1 monocyte adhesion to ECs (P=0.032). Spironolactone dramatically reduced DHT+S1-induced endothelial activation. Pre-treatment of ECs with valsartan did not increase endothelial activation by S1. TNF-α exacerbated S1-induced EC activation and spironolactone abrogated this effect. Analysis of plasma from patients hospitalized with COVID-19 showed concordant higher VCAM-1 in men as compared to women.Interpretation: Androgen exposure promotes spike protein-mediated endothelial injury by increasing markers of inflammation and thrombosis. A beneficial therapeutic effect of the FDA-approved drug spironolactone was observed, supporting a rationale for further evaluation as an adjunct treatment in COVID-19. Funding: This work was supported by the Michigan Biological Research Initiative on Sex Differences in Cardiovascular Disease, COVID-19 Ignitor Award, and University of Michigan Taubman Medical Research Institute.Declaration of Interests: No conflicts of interest, financial or otherwise, are declared by the author(s).Ethics Approval Statement: Study involving measurement of circulating endothelial injury markers in the plasma of COVID-19 patients was approved by the Institutional Review Board (HUM00180521) at the University of Michigan.