Androgen Regulates SARS-CoV-2 Receptor Levels and Is Associated with Severe COVID-19 Symptoms in Men

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has led to a global health crisis, and yet our understanding of the disease pathophysiology and potential treatment options remains limited. SARS-CoV-2 infection occurs through binding and internalization of the viral spike prote...

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Autores principales: Ghazizadeh, Zaniar, Majd, Homa, Richter, Mikayla, Samuel, Ryan, Zekavat, Seyedeh Maryam, Asgharian, Hosseinali, Farahvashi, Sina, Kalantari, Ali, Ramirez, Jonathan, Zhao, Hongyu, Natarajan, Pradeep, Goodarzi, Hani, Fattahi, Faranak
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Cold Spring Harbor Laboratory 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7263488/
https://www.ncbi.nlm.nih.gov/pubmed/32511360
http://dx.doi.org/10.1101/2020.05.12.091082
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author Ghazizadeh, Zaniar
Majd, Homa
Richter, Mikayla
Samuel, Ryan
Zekavat, Seyedeh Maryam
Asgharian, Hosseinali
Farahvashi, Sina
Kalantari, Ali
Ramirez, Jonathan
Zhao, Hongyu
Natarajan, Pradeep
Goodarzi, Hani
Fattahi, Faranak
author_facet Ghazizadeh, Zaniar
Majd, Homa
Richter, Mikayla
Samuel, Ryan
Zekavat, Seyedeh Maryam
Asgharian, Hosseinali
Farahvashi, Sina
Kalantari, Ali
Ramirez, Jonathan
Zhao, Hongyu
Natarajan, Pradeep
Goodarzi, Hani
Fattahi, Faranak
author_sort Ghazizadeh, Zaniar
collection PubMed
description Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has led to a global health crisis, and yet our understanding of the disease pathophysiology and potential treatment options remains limited. SARS-CoV-2 infection occurs through binding and internalization of the viral spike protein to angiotensin converting enzyme 2 (ACE2) on the host cell membrane. Lethal complications are caused by damage and failure of vital organs that express high levels of ACE2, including the lungs, the heart and the kidneys. Here, we established a high-throughput drug screening strategy to identify therapeutic candidates that reduce ACE2 levels in human embryonic stem cell (hESC) derived cardiac cells. Drug target analysis of validated hit compounds, including 5 alpha reductase inhibitors, revealed androgen signaling as a key modulator of ACE2 levels. Treatment with the 5 alpha reductase inhibitor dutasteride reduced ACE2 levels and internalization of recombinant spike receptor binding domain (Spike-RBD) in hESC-derived cardiac cells and human alveolar epithelial cells. Finally, clinical data on coronavirus disease 2019 (COVID-19) patients demonstrated that abnormal androgen states are significantly associated with severe disease complications and cardiac injury as measured by blood troponin T levels. These findings provide important insights on the mechanism of increased disease susceptibility in male COVID-19 patients and identify androgen receptor inhibition as a potential therapeutic strategy.
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spelling pubmed-72634882020-06-07 Androgen Regulates SARS-CoV-2 Receptor Levels and Is Associated with Severe COVID-19 Symptoms in Men Ghazizadeh, Zaniar Majd, Homa Richter, Mikayla Samuel, Ryan Zekavat, Seyedeh Maryam Asgharian, Hosseinali Farahvashi, Sina Kalantari, Ali Ramirez, Jonathan Zhao, Hongyu Natarajan, Pradeep Goodarzi, Hani Fattahi, Faranak bioRxiv Article Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has led to a global health crisis, and yet our understanding of the disease pathophysiology and potential treatment options remains limited. SARS-CoV-2 infection occurs through binding and internalization of the viral spike protein to angiotensin converting enzyme 2 (ACE2) on the host cell membrane. Lethal complications are caused by damage and failure of vital organs that express high levels of ACE2, including the lungs, the heart and the kidneys. Here, we established a high-throughput drug screening strategy to identify therapeutic candidates that reduce ACE2 levels in human embryonic stem cell (hESC) derived cardiac cells. Drug target analysis of validated hit compounds, including 5 alpha reductase inhibitors, revealed androgen signaling as a key modulator of ACE2 levels. Treatment with the 5 alpha reductase inhibitor dutasteride reduced ACE2 levels and internalization of recombinant spike receptor binding domain (Spike-RBD) in hESC-derived cardiac cells and human alveolar epithelial cells. Finally, clinical data on coronavirus disease 2019 (COVID-19) patients demonstrated that abnormal androgen states are significantly associated with severe disease complications and cardiac injury as measured by blood troponin T levels. These findings provide important insights on the mechanism of increased disease susceptibility in male COVID-19 patients and identify androgen receptor inhibition as a potential therapeutic strategy. Cold Spring Harbor Laboratory 2020-05-15 /pmc/articles/PMC7263488/ /pubmed/32511360 http://dx.doi.org/10.1101/2020.05.12.091082 Text en http://creativecommons.org/licenses/by-nc-nd/4.0/It is made available under a CC-BY-NC-ND 4.0 International license (http://creativecommons.org/licenses/by-nc-nd/4.0/) .
spellingShingle Article
Ghazizadeh, Zaniar
Majd, Homa
Richter, Mikayla
Samuel, Ryan
Zekavat, Seyedeh Maryam
Asgharian, Hosseinali
Farahvashi, Sina
Kalantari, Ali
Ramirez, Jonathan
Zhao, Hongyu
Natarajan, Pradeep
Goodarzi, Hani
Fattahi, Faranak
Androgen Regulates SARS-CoV-2 Receptor Levels and Is Associated with Severe COVID-19 Symptoms in Men
title Androgen Regulates SARS-CoV-2 Receptor Levels and Is Associated with Severe COVID-19 Symptoms in Men
title_full Androgen Regulates SARS-CoV-2 Receptor Levels and Is Associated with Severe COVID-19 Symptoms in Men
title_fullStr Androgen Regulates SARS-CoV-2 Receptor Levels and Is Associated with Severe COVID-19 Symptoms in Men
title_full_unstemmed Androgen Regulates SARS-CoV-2 Receptor Levels and Is Associated with Severe COVID-19 Symptoms in Men
title_short Androgen Regulates SARS-CoV-2 Receptor Levels and Is Associated with Severe COVID-19 Symptoms in Men
title_sort androgen regulates sars-cov-2 receptor levels and is associated with severe covid-19 symptoms in men
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7263488/
https://www.ncbi.nlm.nih.gov/pubmed/32511360
http://dx.doi.org/10.1101/2020.05.12.091082
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