HSP90 Inhibitors Modulate SARS-CoV-2 Spike Protein Subunit 1-Induced Human Pulmonary Microvascular Endothelial Activation and Barrier Dysfunction.

Autor:	Colunga Biancatelli RML; Frank Reidy Research Center for Bioelectrics, Old Dominion University, Norfolk, VA, United States., Solopov PA; Frank Reidy Research Center for Bioelectrics, Old Dominion University, Norfolk, VA, United States., Gregory B; Frank Reidy Research Center for Bioelectrics, Old Dominion University, Norfolk, VA, United States., Khodour Y; Frank Reidy Research Center for Bioelectrics, Old Dominion University, Norfolk, VA, United States., Catravas JD; Frank Reidy Research Center for Bioelectrics, Old Dominion University, Norfolk, VA, United States.; School of Medical Diagnostic & Translational Sciences, College of Health Sciences, Old Dominion University, Norfolk, VA, United States.
Jazyk:	angličtina
Zdroj:	Frontiers in physiology [Front Physiol] 2022 Mar 21; Vol. 13, pp. 812199. Date of Electronic Publication: 2022 Mar 21 (Print Publication: 2022).
DOI:	10.3389/fphys.2022.812199
Abstrakt:	Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has caused more than 5 million deaths worldwide. Multiple reports indicate that the endothelium is involved during SARS-Cov-2-related disease (COVID-19). Indeed, COVID-19 patients display increased thrombophilia with arterial and venous embolism and lung microcapillary thrombotic disease as major determinants of deaths. The pathophysiology of endothelial dysfunction in COVID-19 is not completely understood. We have investigated the role of subunit 1 of the SARS-CoV-2 spike protein (S1SP) in eliciting endothelial barrier dysfunction, characterized dose and time relationships, and tested the hypothesis that heat shock protein 90 (HSP90) inhibitors would prevent and repair such injury. S1SP activated (phosphorylated) IKBα, STAT3, and AKT and reduced the expression of intercellular junctional proteins, occludin, and VE-cadherin. HSP90 inhibitors (AT13387 and AUY-922) prevented endothelial barrier dysfunction and hyperpermeability and reduced IKBα and AKT activation. These two inhibitors also blocked S1SP-mediated barrier dysfunction and loss of VE-cadherin. These data suggest that spike protein subunit 1 can elicit, by itself, direct injury to the endothelium and suggest a role of HSP90 inhibitors in preserving endothelial functionality. Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. (Copyright © 2022 Colunga Biancatelli, Solopov, Gregory, Khodour and Catravas.)
Databáze:	MEDLINE
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