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
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 morta...
| Main Authors: | , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2021-10-01
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| Series: | Redox Biology |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2213231721002585 |
| _version_ | 1828918746981335040 |
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| author | Ji Youn Youn Yixuan Zhang Yusi Wu Maxime Cannesson Hua Cai |
| author_facet | Ji Youn Youn Yixuan Zhang Yusi Wu Maxime Cannesson Hua Cai |
| author_sort | Ji Youn Youn |
| collection | DOAJ |
| description | 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, 17β-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 17β-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. |
| first_indexed | 2024-12-13T21:15:45Z |
| format | Article |
| id | doaj.art-b7cc2dc0af6a442aa102ca8b0f4115ec |
| institution | Directory Open Access Journal |
| issn | 2213-2317 |
| language | English |
| last_indexed | 2024-12-13T21:15:45Z |
| publishDate | 2021-10-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Redox Biology |
| spelling | doaj.art-b7cc2dc0af6a442aa102ca8b0f4115ec2022-12-21T23:31:15ZengElsevierRedox Biology2213-23172021-10-0146102099Therapeutic 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 cellsJi Youn Youn0Yixuan Zhang1Yusi Wu2Maxime Cannesson3Hua Cai4Division 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, USADivision 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, USADivision 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, USADivision 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, USACorresponding author. David Geffen School of Medicine, University of California, Los Angeles, USA.; 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, USAThe 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, 17β-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 17β-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.http://www.sciencedirect.com/science/article/pii/S2213231721002585COVID-19EstrogenIL-6SARS CoV-2 spike proteinEndothelial cellsOxidative stress |
| spellingShingle | Ji Youn Youn Yixuan Zhang Yusi Wu Maxime Cannesson Hua Cai 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 Redox Biology COVID-19 Estrogen IL-6 SARS CoV-2 spike protein Endothelial cells Oxidative stress |
| title | 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 |
| title_full | 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 |
| title_fullStr | 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 |
| title_full_unstemmed | 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 |
| title_short | 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 |
| title_sort | 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 |
| topic | COVID-19 Estrogen IL-6 SARS CoV-2 spike protein Endothelial cells Oxidative stress |
| url | http://www.sciencedirect.com/science/article/pii/S2213231721002585 |
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