HSP90 Inhibitors Modulate SARS-CoV-2 Spike Protein Subunit 1-Induced Human Pulmonary Microvascular Endothelial Activation and Barrier Dysfunction
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 em...
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Frontiers Media S.A.
2022-03-01
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| Series: | Frontiers in Physiology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fphys.2022.812199/full |
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| author | Ruben Manuel Luciano Colunga Biancatelli Pavel A. Solopov Betsy Gregory Yara Khodour John D. Catravas John D. Catravas |
| author_facet | Ruben Manuel Luciano Colunga Biancatelli Pavel A. Solopov Betsy Gregory Yara Khodour John D. Catravas John D. Catravas |
| author_sort | Ruben Manuel Luciano Colunga Biancatelli |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-13T20:23:25Z |
| format | Article |
| id | doaj.art-fd8a151fb5bd458fb5b96d5fc2a0b27b |
| institution | Directory Open Access Journal |
| issn | 1664-042X |
| language | English |
| last_indexed | 2024-12-13T20:23:25Z |
| publishDate | 2022-03-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Physiology |
| spelling | doaj.art-fd8a151fb5bd458fb5b96d5fc2a0b27b2022-12-21T23:32:38ZengFrontiers Media S.A.Frontiers in Physiology1664-042X2022-03-011310.3389/fphys.2022.812199812199HSP90 Inhibitors Modulate SARS-CoV-2 Spike Protein Subunit 1-Induced Human Pulmonary Microvascular Endothelial Activation and Barrier DysfunctionRuben Manuel Luciano Colunga Biancatelli0Pavel A. Solopov1Betsy Gregory2Yara Khodour3John D. Catravas4John D. Catravas5Frank Reidy Research Center for Bioelectrics, Old Dominion University, Norfolk, VA, United StatesFrank Reidy Research Center for Bioelectrics, Old Dominion University, Norfolk, VA, United StatesFrank Reidy Research Center for Bioelectrics, Old Dominion University, Norfolk, VA, United StatesFrank Reidy Research Center for Bioelectrics, Old Dominion University, Norfolk, VA, United StatesFrank Reidy Research Center for Bioelectrics, Old Dominion University, Norfolk, VA, United StatesSchool of Medical Diagnostic & Translational Sciences, College of Health Sciences, Old Dominion University, Norfolk, VA, United StatesSevere 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.https://www.frontiersin.org/articles/10.3389/fphys.2022.812199/fullSARS-CoV-2spike proteinendothelial dysfunctionheat shock proteinsHSP90 inhibitorsAUY-922 |
| spellingShingle | Ruben Manuel Luciano Colunga Biancatelli Pavel A. Solopov Betsy Gregory Yara Khodour John D. Catravas John D. Catravas HSP90 Inhibitors Modulate SARS-CoV-2 Spike Protein Subunit 1-Induced Human Pulmonary Microvascular Endothelial Activation and Barrier Dysfunction Frontiers in Physiology SARS-CoV-2 spike protein endothelial dysfunction heat shock proteins HSP90 inhibitors AUY-922 |
| title | HSP90 Inhibitors Modulate SARS-CoV-2 Spike Protein Subunit 1-Induced Human Pulmonary Microvascular Endothelial Activation and Barrier Dysfunction |
| title_full | HSP90 Inhibitors Modulate SARS-CoV-2 Spike Protein Subunit 1-Induced Human Pulmonary Microvascular Endothelial Activation and Barrier Dysfunction |
| title_fullStr | HSP90 Inhibitors Modulate SARS-CoV-2 Spike Protein Subunit 1-Induced Human Pulmonary Microvascular Endothelial Activation and Barrier Dysfunction |
| title_full_unstemmed | HSP90 Inhibitors Modulate SARS-CoV-2 Spike Protein Subunit 1-Induced Human Pulmonary Microvascular Endothelial Activation and Barrier Dysfunction |
| title_short | HSP90 Inhibitors Modulate SARS-CoV-2 Spike Protein Subunit 1-Induced Human Pulmonary Microvascular Endothelial Activation and Barrier Dysfunction |
| title_sort | hsp90 inhibitors modulate sars cov 2 spike protein subunit 1 induced human pulmonary microvascular endothelial activation and barrier dysfunction |
| topic | SARS-CoV-2 spike protein endothelial dysfunction heat shock proteins HSP90 inhibitors AUY-922 |
| url | https://www.frontiersin.org/articles/10.3389/fphys.2022.812199/full |
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