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Molecular Analysis of SARS-CoV-2 Spike Protein-Induced Endothelial Cell Permeability and vWF Secretion

Yuexi Guo, Venkat Kanamarlapudi Orcid Logo

International Journal of Molecular Sciences, Volume: 24, Issue: 6, Start page: 5664

Swansea University Author: Venkat Kanamarlapudi Orcid Logo

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DOI (Published version): 10.3390/ijms24065664

Abstract

Coronavirus disease COVID-19, which is caused by severe acute respiratory syndrome coronavirus SARS-CoV-2, has become a worldwide pandemic in recent years. In addition to being a respiratory disease, COVID-19 is a ‘vascular disease’ since it causes a leaky vascular barrier and increases blood clotti...

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Published in: International Journal of Molecular Sciences
ISSN: 1422-0067
Published: MDPI AG 2023
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URI: https://cronfa.swan.ac.uk/Record/cronfa63098
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spelling 2024-02-02T08:34:03.5757145 v2 63098 2023-04-06 Molecular Analysis of SARS-CoV-2 Spike Protein-Induced Endothelial Cell Permeability and vWF Secretion 63741801137148abfa4c00cd547dcdfa 0000-0002-8739-1483 Venkat Kanamarlapudi Venkat Kanamarlapudi true false 2023-04-06 MEDS Coronavirus disease COVID-19, which is caused by severe acute respiratory syndrome coronavirus SARS-CoV-2, has become a worldwide pandemic in recent years. In addition to being a respiratory disease, COVID-19 is a ‘vascular disease’ since it causes a leaky vascular barrier and increases blood clotting by elevating von Willebrand factor (vWF) levels in the blood. In this study, we analyzed in vitro how the SARS-CoV-2 spike protein S1 induces endothelial cell (EC) permeability and its vWF secretion, and the underlying molecular mechanism for it. We showed that the SARS-CoV-2 spike protein S1 receptor-binding domain (RBD) is sufficient to induce endothelial permeability and vWF-secretion through the angiotensin-converting enzyme (ACE)2 in an ADP-ribosylation factor (ARF)6 activation-dependent manner. However, the mutants, including those in South African and South Californian variants of SARS-CoV-2, in the spike protein did not affect its induced EC permeability and vWF secretion. In addition, we have identified a signaling cascade downstream of ACE2 for the SARS-CoV-2 spike protein-induced EC permeability and its vWF secretion by using pharmacological inhibitors. The knowledge gained from this study could be useful in developing novel drugs or repurposing existing drugs for treating infections of SARS-CoV-2, particularly those strains that respond poorly to the existing vaccines. Journal Article International Journal of Molecular Sciences 24 6 5664 MDPI AG 1422-0067 COVID-19; SARS-CoV-2; spike protein; RBD; vWF; endothelial permeability; ACE2; ARF6; signaling 16 3 2023 2023-03-16 10.3390/ijms24065664 http://dx.doi.org/10.3390/ijms24065664 COLLEGE NANME Medical School COLLEGE CODE MEDS Swansea University 2024-02-02T08:34:03.5757145 2023-04-06T17:50:14.2659457 Faculty of Medicine, Health and Life Sciences Swansea University Medical School - Medicine Yuexi Guo 1 Venkat Kanamarlapudi 0000-0002-8739-1483 2 63098__27414__deccbf6a0c6144eead715be87b0baddf.pdf 63098.pdf 2023-05-10T15:20:19.2574876 Output 2313782 application/pdf Version of Record true © 2023 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/). true eng https://creativecommons.org/licenses/by/4.0/
title Molecular Analysis of SARS-CoV-2 Spike Protein-Induced Endothelial Cell Permeability and vWF Secretion
spellingShingle Molecular Analysis of SARS-CoV-2 Spike Protein-Induced Endothelial Cell Permeability and vWF Secretion
Venkat Kanamarlapudi
title_short Molecular Analysis of SARS-CoV-2 Spike Protein-Induced Endothelial Cell Permeability and vWF Secretion
title_full Molecular Analysis of SARS-CoV-2 Spike Protein-Induced Endothelial Cell Permeability and vWF Secretion
title_fullStr Molecular Analysis of SARS-CoV-2 Spike Protein-Induced Endothelial Cell Permeability and vWF Secretion
title_full_unstemmed Molecular Analysis of SARS-CoV-2 Spike Protein-Induced Endothelial Cell Permeability and vWF Secretion
title_sort Molecular Analysis of SARS-CoV-2 Spike Protein-Induced Endothelial Cell Permeability and vWF Secretion
author_id_str_mv 63741801137148abfa4c00cd547dcdfa
author_id_fullname_str_mv 63741801137148abfa4c00cd547dcdfa_***_Venkat Kanamarlapudi
author Venkat Kanamarlapudi
author2 Yuexi Guo
Venkat Kanamarlapudi
format Journal article
container_title International Journal of Molecular Sciences
container_volume 24
container_issue 6
container_start_page 5664
publishDate 2023
institution Swansea University
issn 1422-0067
doi_str_mv 10.3390/ijms24065664
publisher MDPI AG
college_str Faculty of Medicine, Health and Life Sciences
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hierarchy_top_id facultyofmedicinehealthandlifesciences
hierarchy_top_title Faculty of Medicine, Health and Life Sciences
hierarchy_parent_id facultyofmedicinehealthandlifesciences
hierarchy_parent_title Faculty of Medicine, Health and Life Sciences
department_str Swansea University Medical School - Medicine{{{_:::_}}}Faculty of Medicine, Health and Life Sciences{{{_:::_}}}Swansea University Medical School - Medicine
url http://dx.doi.org/10.3390/ijms24065664
document_store_str 1
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description Coronavirus disease COVID-19, which is caused by severe acute respiratory syndrome coronavirus SARS-CoV-2, has become a worldwide pandemic in recent years. In addition to being a respiratory disease, COVID-19 is a ‘vascular disease’ since it causes a leaky vascular barrier and increases blood clotting by elevating von Willebrand factor (vWF) levels in the blood. In this study, we analyzed in vitro how the SARS-CoV-2 spike protein S1 induces endothelial cell (EC) permeability and its vWF secretion, and the underlying molecular mechanism for it. We showed that the SARS-CoV-2 spike protein S1 receptor-binding domain (RBD) is sufficient to induce endothelial permeability and vWF-secretion through the angiotensin-converting enzyme (ACE)2 in an ADP-ribosylation factor (ARF)6 activation-dependent manner. However, the mutants, including those in South African and South Californian variants of SARS-CoV-2, in the spike protein did not affect its induced EC permeability and vWF secretion. In addition, we have identified a signaling cascade downstream of ACE2 for the SARS-CoV-2 spike protein-induced EC permeability and its vWF secretion by using pharmacological inhibitors. The knowledge gained from this study could be useful in developing novel drugs or repurposing existing drugs for treating infections of SARS-CoV-2, particularly those strains that respond poorly to the existing vaccines.
published_date 2023-03-16T08:24:41Z
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