Therapeutic application of estrogen for COVID-19: Attenuation of SARS-CoV-2 spike protein and IL-6 stimulated, ACE2-dependent NOX2 activation, ROS production and MCP-1 upregulation in endothelial cells

• DOI: 10.1016/j.redox.2021.102099
• Publication Date: 2021-08-17T18:20:08Z
• Authors: Ji Youn Youn; Yixuan Zhang; Yusi Wu; Maxime Cannesson; Hua Cai
• Keywords: Endothelial Activation; Endothelial Dysfunction

The outbreak of COVID-19 has remained uncontained with urgent need for robust therapeutics. We have previously reported sex difference the first time indicating male predisposition. Males are more susceptible than females, and often to develop into severe cases higher mortality. This predisposition is potentially linked prevalence cigarette smoking. Nonetheless, we found that smoking extract (CSE) had no effect on angiotensin converting enzyme 2 (ACE2) transmembrane protease serine (TMPRSS2) expression in endothelial cells. otherwise observed worse outcomes smokers likely baseline respiratory diseases associated chronic Instead, hypothesized estrogen mediated protection might underlie lower morbidity, severity mortality females. Of note, inflammation barrier dysfunction major mediators disease progression, development acute distress syndrome (ARDS) multi-organ failure patients COVID-19. Therefore, investigated potential protective effects cells against oxidative stress induced by interleukin-6 (IL-6) SARS-CoV-2 spike protein (S protein). Indeed, 17β-estradiol completely reversed S protein-induced selective activation NADPH oxidase isoform (NOX2) reactive oxygen species (ROS) production ACE2-dependent, as well ACE2 upregulation induction pro-inflammatory gene monocyte chemoattractant protein-1 (MCP-1) effectively attenuate dysfunction. Effects IL-6 activating NOX2-dependent ROS MCP-1 were also attenuated 17β-estradiol. co-treatment CSE additional stimulated stress, confirming current status unrelated smokers. These data indicate can serve a novel therapy via inhibition initial viral responses attenuation cytokine storm dysfunction, substantially alleviate disease, especially men post-menopause women. Short-term administration therefore be readily applied clinical management therapeutic option.