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

Ruben Manuel Luciano Colunga Biancatelli; Pavel A Solopov; Betsy Gregory; Yara Khodour; John D Catravas

doi:10.3389/fphys.2022.812199

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

Front Physiol. 2022 Mar 21:13:812199. doi: 10.3389/fphys.2022.812199. eCollection 2022.

Authors

Ruben Manuel Luciano Colunga Biancatelli¹, Pavel A Solopov¹, Betsy Gregory¹, Yara Khodour¹, John D Catravas^{1

2}

Affiliations

¹ Frank Reidy Research Center for Bioelectrics, Old Dominion University, Norfolk, VA, United States.
² School of Medical Diagnostic & Translational Sciences, College of Health Sciences, Old Dominion University, Norfolk, VA, United States.

Abstract

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.

Keywords: AT13387; AUY-922; HSP90 inhibitors; SARS-CoV-2; endothelial dysfunction; heat shock proteins; spike protein.