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SARS-CoV-2 Spike Protein Impairs Endothelial Function via Downregulation of ACE2

Yuyang Lei, Jiao Zhang, Cara R. Schiavon, Ming He, Lili Chen, Hui Shen, Yichi Zhang, Qian Yin, Yoshitake Cho, Leonardo Andrade, Gerry S. Shadel, Mark Hepokoski, Ting Lei, Hongliang Wang, Jin Zhang, Jason X.-J. Yuan, Atul Malhotra, View ORCID ProfileUri Manor, Shengpeng Wang, Zu-Yi Yuan, John Y-J. Shyy
doi: https://doi.org/10.1101/2020.12.04.409144
Yuyang Lei
1Department of Cardiology, First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, China
2Cardiovascular Research Center, School of Basic Medical Sciences, Xi’an Jiaotong University Health Science Center, Xi’an, China
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Jiao Zhang
1Department of Cardiology, First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, China
2Cardiovascular Research Center, School of Basic Medical Sciences, Xi’an Jiaotong University Health Science Center, Xi’an, China
3Division of Cardiology, Department of Medicine, University of California, San Diego, La Jolla, CA
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Cara R. Schiavon
4Waitt Advanced Biophotonics Center, Salk Institute for Biological Studies, La Jolla, CA
5Molecular and Cellular Biology Laboratory, Salk Institute for Biological Studies, La Jolla, CA, USA
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Ming He
3Division of Cardiology, Department of Medicine, University of California, San Diego, La Jolla, CA
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Lili Chen
2Cardiovascular Research Center, School of Basic Medical Sciences, Xi’an Jiaotong University Health Science Center, Xi’an, China
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Hui Shen
3Division of Cardiology, Department of Medicine, University of California, San Diego, La Jolla, CA
6Department of Cardiology, the Affiliated Hospital of Yangzhou University, Yangzhou, China
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Yichi Zhang
3Division of Cardiology, Department of Medicine, University of California, San Diego, La Jolla, CA
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Qian Yin
2Cardiovascular Research Center, School of Basic Medical Sciences, Xi’an Jiaotong University Health Science Center, Xi’an, China
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Yoshitake Cho
3Division of Cardiology, Department of Medicine, University of California, San Diego, La Jolla, CA
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Leonardo Andrade
4Waitt Advanced Biophotonics Center, Salk Institute for Biological Studies, La Jolla, CA
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Gerry S. Shadel
5Molecular and Cellular Biology Laboratory, Salk Institute for Biological Studies, La Jolla, CA, USA
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Mark Hepokoski
7Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, University of California, San Diego, La Jolla, CA
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Ting Lei
8Department of Pathology, School of Basic Medical Sciences, Xi’an Jiaotong University Health Science Center, Xi’an, China
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Hongliang Wang
9Department of pathogen biology and immunology, School of Basic Medical Sciences, Xi’an Jiaotong University Health Science Center, Xi’an, China
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Jin Zhang
10Department of Pharmacology, University of California, San Diego, La Jolla, CA
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Jason X.-J. Yuan
7Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, University of California, San Diego, La Jolla, CA
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Atul Malhotra
7Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, University of California, San Diego, La Jolla, CA
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Uri Manor
4Waitt Advanced Biophotonics Center, Salk Institute for Biological Studies, La Jolla, CA
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  • ORCID record for Uri Manor
  • For correspondence: jshyy@health.ucsd.edu zuyiyuan@mail.xjtu.edu.cn shengpeng.wang@xjtu.edu.cn umanor@salk.edu
Shengpeng Wang
2Cardiovascular Research Center, School of Basic Medical Sciences, Xi’an Jiaotong University Health Science Center, Xi’an, China
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  • For correspondence: jshyy@health.ucsd.edu zuyiyuan@mail.xjtu.edu.cn shengpeng.wang@xjtu.edu.cn umanor@salk.edu
Zu-Yi Yuan
1Department of Cardiology, First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, China
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  • For correspondence: jshyy@health.ucsd.edu zuyiyuan@mail.xjtu.edu.cn shengpeng.wang@xjtu.edu.cn umanor@salk.edu
John Y-J. Shyy
3Division of Cardiology, Department of Medicine, University of California, San Diego, La Jolla, CA
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  • For correspondence: jshyy@health.ucsd.edu zuyiyuan@mail.xjtu.edu.cn shengpeng.wang@xjtu.edu.cn umanor@salk.edu
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Abstract

Coronavirus disease 2019 (COVID-19) includes the cardiovascular complications in addition to respiratory disease. SARS-CoV-2 infection impairs endothelial function and induces vascular inflammation, leading to endotheliitis. SARS-CoV-2 infection relies on the binding of Spike glycoprotein (S protein) to angiotensin converting enzyme 2 (ACE2) in the host cells. We show here that S protein alone can damage vascular endothelial cells (ECs) in vitro and in vivo, manifested by impaired mitochondrial function, decreased ACE2 expression and eNOS activity, and increased glycolysis. The underlying mechanism involves S protein downregulation of AMPK and upregulation of MDM2, causing ACE2 destabilization. Thus, the S protein-exerted vascular endothelial damage via ACE2 downregulation overrides the decreased virus infectivity.

Competing Interest Statement

The authors have declared no competing interest.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
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Posted December 04, 2020.
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SARS-CoV-2 Spike Protein Impairs Endothelial Function via Downregulation of ACE2
Yuyang Lei, Jiao Zhang, Cara R. Schiavon, Ming He, Lili Chen, Hui Shen, Yichi Zhang, Qian Yin, Yoshitake Cho, Leonardo Andrade, Gerry S. Shadel, Mark Hepokoski, Ting Lei, Hongliang Wang, Jin Zhang, Jason X.-J. Yuan, Atul Malhotra, Uri Manor, Shengpeng Wang, Zu-Yi Yuan, John Y-J. Shyy
bioRxiv 2020.12.04.409144; doi: https://doi.org/10.1101/2020.12.04.409144
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SARS-CoV-2 Spike Protein Impairs Endothelial Function via Downregulation of ACE2
Yuyang Lei, Jiao Zhang, Cara R. Schiavon, Ming He, Lili Chen, Hui Shen, Yichi Zhang, Qian Yin, Yoshitake Cho, Leonardo Andrade, Gerry S. Shadel, Mark Hepokoski, Ting Lei, Hongliang Wang, Jin Zhang, Jason X.-J. Yuan, Atul Malhotra, Uri Manor, Shengpeng Wang, Zu-Yi Yuan, John Y-J. Shyy
bioRxiv 2020.12.04.409144; doi: https://doi.org/10.1101/2020.12.04.409144

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