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

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 endotheli...

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Veröffentlicht in:Viruses Jg. 13; H. 11; S. 2209
Hauptverfasser: Kumar, Nitin, Zuo, Yu, Yalavarthi, Srilakshmi, Hunker, Kristina L., Knight, Jason S., Kanthi, Yogendra, Obi, Andrea T., Ganesh, Santhi K.
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Sprache:Englisch
Veröffentlicht: Switzerland MDPI AG 03.11.2021
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ISSN:1999-4915, 1999-4915
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Abstract 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-α) 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-α 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.
AbstractList 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-α) 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-α 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.
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-α) 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 ( < 0.05), and increased THP-1 monocyte adhesion to ECs ( = 0.032). Spironolactone dramatically reduced DHT+S1-induced endothelial activation. TNF-α 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.
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-α) 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-α 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.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-α) 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-α 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.
Author Obi, Andrea T.
Kumar, Nitin
Kanthi, Yogendra
Knight, Jason S.
Zuo, Yu
Yalavarthi, Srilakshmi
Hunker, Kristina L.
Ganesh, Santhi K.
AuthorAffiliation 3 Department of Internal Medicine, Division of Rheumatology, University of Michigan, Ann Arbor, MI 48109, USA; yzu@med.umich.edu (Y.Z.); syalavar@med.umich.edu (S.Y.); jsknight@med.umich.edu (J.S.K.)
1 Department of Internal Medicine, Division of Cardiovascular Medicine, University of Michigan, Ann Arbor, MI 48109, USA; kumarni@med.umich.edu (N.K.); klhunker@med.umich.edu (K.L.H.); yogen.kanthi@nih.gov (Y.K.)
2 Department of Human Genetics, University of Michigan, Ann Arbor, MI 48109, USA
4 National Heart, Lung and Blood Institute, Bethesda, MD 20892, USA
5 Section of Vascular Surgery, Department of Surgery, University of Michigan, Ann Arbor, MI 48109, USA; easta@med.umich.edu
AuthorAffiliation_xml – name: 4 National Heart, Lung and Blood Institute, Bethesda, MD 20892, USA
– name: 3 Department of Internal Medicine, Division of Rheumatology, University of Michigan, Ann Arbor, MI 48109, USA; yzu@med.umich.edu (Y.Z.); syalavar@med.umich.edu (S.Y.); jsknight@med.umich.edu (J.S.K.)
– name: 5 Section of Vascular Surgery, Department of Surgery, University of Michigan, Ann Arbor, MI 48109, USA; easta@med.umich.edu
– name: 1 Department of Internal Medicine, Division of Cardiovascular Medicine, University of Michigan, Ann Arbor, MI 48109, USA; kumarni@med.umich.edu (N.K.); klhunker@med.umich.edu (K.L.H.); yogen.kanthi@nih.gov (Y.K.)
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  surname: Ganesh
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BackLink https://www.ncbi.nlm.nih.gov/pubmed/34835015$$D View this record in MEDLINE/PubMed
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Copyright_xml – notice: 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.
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Issue 11
Keywords COVID-19
E-selectin
androgen
angiotensin receptor blocker
spironolactone
endothelial injury
Language English
License Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
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  year: 2021
  text: 20211103
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PublicationTitle Viruses
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SSID ssj0066907
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Snippet Men are disproportionately affected by the coronavirus disease-2019 (COVID-19), and face higher odds of severe illness and death compared to women. The...
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StartPage 2209
SubjectTerms adhesion
androgen
Androgens
Angiotensin Receptor Antagonists - pharmacology
angiotensin receptor blocker
antagonism
cell adhesion
Cell adhesion & migration
Cell adhesion molecules
Cell Adhesion Molecules - blood
Cells, Cultured
Coronaviruses
COVID-19
COVID-19 - pathology
COVID-19 - physiopathology
COVID-19 - virology
COVID-19 infection
death
Dihydrotestosterone
Dihydrotestosterone - pharmacology
disease severity
Disease transmission
E-selectin
Endothelial cells
endothelial injury
Endothelium
Endothelium, Vascular - drug effects
Endothelium, Vascular - metabolism
Endothelium, Vascular - pathology
Female
Fibrin
Gender differences
Heart failure
Humans
Infections
Inflammation
Intercellular adhesion molecule 1
Male
mineralocorticoid receptors
Monocytes
Pandemics
Proteins
SARS-CoV-2 - physiology
Severe acute respiratory syndrome coronavirus 2
Sex Characteristics
Spike Glycoprotein, Coronavirus - physiology
Spike protein
spironolactone
Spironolactone - pharmacology
therapeutics
tumor necrosis factor-alpha
Tumor Necrosis Factor-alpha - pharmacology
Tumor Necrosis Factor-alpha - physiology
Tumor necrosis factor-TNF
Tumor necrosis factor-α
Valsartan - pharmacology
Vascular cell adhesion molecule 1
vascular cell adhesion molecules
Viral infections
Women
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Title SARS-CoV-2 Spike Protein S1-Mediated Endothelial Injury and Pro-Inflammatory State Is Amplified by Dihydrotestosterone and Prevented by Mineralocorticoid Antagonism
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