PMID- 34509916 OWN - NLM STAT- MEDLINE DCOM- 20210927 LR - 20221207 IS - 2213-2317 (Electronic) IS - 2213-2317 (Linking) VI - 46 DP - 2021 Oct TI - 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. PG - 102099 LID - S2213-2317(21)00258-5 [pii] LID - 10.1016/j.redox.2021.102099 [doi] LID - 102099 AB - The outbreak of COVID-19 has remained uncontained with urgent need for robust therapeutics. We have previously reported sex difference of COVID-19 for the first time indicating male predisposition. Males are more susceptible than females, and more often to develop into severe cases with higher mortality. This predisposition is potentially linked to higher prevalence of cigarette smoking. Nonetheless, we found for the first time that cigarette smoking extract (CSE) had no effect on angiotensin converting enzyme 2 (ACE2) and transmembrane protease serine 2 (TMPRSS2) expression in endothelial cells. The otherwise observed worse outcomes in smokers is likely linked to baseline respiratory diseases associated with chronic smoking. Instead, we hypothesized that estrogen mediated protection might underlie lower morbidity, severity and mortality of COVID-19 in females. Of note, endothelial inflammation and barrier dysfunction are major mediators of disease progression, and development of acute respiratory distress syndrome (ARDS) and multi-organ failure in patients with COVID-19. Therefore, we investigated potential protective effects of estrogen on endothelial cells against oxidative stress induced by interleukin-6 (IL-6) and SARS-CoV-2 spike protein (S protein). Indeed, 17beta-estradiol completely reversed S protein-induced selective activation of NADPH oxidase isoform 2 (NOX2) and reactive oxygen species (ROS) production that are ACE2-dependent, as well as ACE2 upregulation and induction of pro-inflammatory gene monocyte chemoattractant protein-1 (MCP-1) in endothelial cells to effectively attenuate endothelial dysfunction. Effects of IL-6 on activating NOX2-dependent ROS production and upregulation of MCP-1 were also completely attenuated by 17beta-estradiol. Of note, co-treatment with CSE had no additional effects on S protein stimulated endothelial oxidative stress, confirming that current smoking status is likely unrelated to more severe disease in chronic smokers. These data indicate that estrogen can serve as a novel therapy for patients with COVID-19 via inhibition of initial viral responses and attenuation of cytokine storm induced endothelial dysfunction, to substantially alleviate morbidity, severity and mortality of the disease, especially in men and post-menopause women. Short-term administration of estrogen can therefore be readily applied to the clinical management of COVID-19 as a robust therapeutic option. CI - Copyright (c) 2021. Published by Elsevier B.V. FAU - Youn, Ji Youn AU - Youn JY AD - Division of Molecular Medicine, Department of Anesthesiology and Perioperative Medicine, Division of Cardiology, Department of Medicine, David Geffen School of Medicine at University of California Los Angeles, USA. FAU - Zhang, Yixuan AU - Zhang Y AD - Division of Molecular Medicine, Department of Anesthesiology and Perioperative Medicine, Division of Cardiology, Department of Medicine, David Geffen School of Medicine at University of California Los Angeles, USA. FAU - Wu, Yusi AU - Wu Y AD - Division of Molecular Medicine, Department of Anesthesiology and Perioperative Medicine, Division of Cardiology, Department of Medicine, David Geffen School of Medicine at University of California Los Angeles, USA. FAU - Cannesson, Maxime AU - Cannesson M AD - Division of Molecular Medicine, Department of Anesthesiology and Perioperative Medicine, Division of Cardiology, Department of Medicine, David Geffen School of Medicine at University of California Los Angeles, USA. FAU - Cai, Hua AU - Cai H AD - Division of Molecular Medicine, Department of Anesthesiology and Perioperative Medicine, Division of Cardiology, Department of Medicine, David Geffen School of Medicine at University of California Los Angeles, USA. Electronic address: hcai@mednet.ucla.edu. LA - eng GR - R01 HL142951/HL/NHLBI NIH HHS/United States GR - R01 HL154754/HL/NHLBI NIH HHS/United States GR - R01 HL162407/HL/NHLBI NIH HHS/United States GR - R01 HL088975/HL/NHLBI NIH HHS/United States GR - R01 HL077440/HL/NHLBI NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural DEP - 20210817 PL - Netherlands TA - Redox Biol JT - Redox biology JID - 101605639 RN - 0 (Chemokine CCL2) RN - 0 (Estrogens) RN - 0 (Interleukin-6) RN - 0 (Reactive Oxygen Species) RN - 0 (Spike Glycoprotein, Coronavirus) RN - 0 (spike protein, SARS-CoV-2) RN - EC 1.6.3.- (CYBB protein, human) RN - EC 1.6.3.- (NADPH Oxidase 2) RN - EC 3.4.17.23 (ACE2 protein, human) RN - EC 3.4.17.23 (Angiotensin-Converting Enzyme 2) SB - IM MH - Angiotensin-Converting Enzyme 2/genetics MH - *COVID-19/metabolism MH - Chemokine CCL2/genetics MH - Endothelial Cells/metabolism MH - Estrogens/*therapeutic use MH - Female MH - Humans MH - Interleukin-6/genetics/metabolism MH - Male MH - NADPH Oxidase 2 MH - Reactive Oxygen Species/metabolism MH - SARS-CoV-2 MH - *Spike Glycoprotein, Coronavirus/genetics/metabolism MH - Up-Regulation MH - *COVID-19 Drug Treatment PMC - PMC8372492 OTO - NOTNLM OT - ACE2 OT - COVID-19 OT - Endothelial cells OT - Estrogen OT - IL-6 OT - MCP-1 OT - NOX2 OT - Oxidative stress OT - SARS CoV-2 spike protein COIS- The authors declare no conflicts of interests for this work. EDAT- 2021/09/13 06:00 MHDA- 2021/09/28 06:00 PMCR- 2021/08/17 CRDT- 2021/09/12 20:58 PHST- 2021/05/24 00:00 [received] PHST- 2021/08/10 00:00 [revised] PHST- 2021/08/11 00:00 [accepted] PHST- 2021/09/13 06:00 [pubmed] PHST- 2021/09/28 06:00 [medline] PHST- 2021/09/12 20:58 [entrez] PHST- 2021/08/17 00:00 [pmc-release] AID - S2213-2317(21)00258-5 [pii] AID - 102099 [pii] AID - 10.1016/j.redox.2021.102099 [doi] PST - ppublish SO - Redox Biol. 2021 Oct;46:102099. doi: 10.1016/j.redox.2021.102099. Epub 2021 Aug 17.