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

Area of Science:

• Vascular Biology
• Virology
• Molecular Medicine

Background:

• Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has led to millions of deaths globally.
• Endothelial involvement in COVID-19 pathogenesis is increasingly recognized, with thrombophilia and microvascular thrombosis being key factors.
• The precise mechanisms of COVID-19-induced endothelial dysfunction remain unclear.

Purpose of the Study:

• To investigate the role of SARS-CoV-2 spike protein subunit 1 (S1SP) in endothelial barrier dysfunction.
• To characterize the dose and time-dependent effects of S1SP on endothelial cells.
• To evaluate the therapeutic potential of heat shock protein 90 (HSP90) inhibitors in preventing and repairing S1SP-induced endothelial injury.

Main Methods:

• In vitro studies using endothelial cells exposed to S1SP.
• Analysis of signaling pathways including IKBα, STAT3, and AKT phosphorylation.
• Assessment of intercellular junctional proteins (occludin, VE-cadherin) expression.
• Treatment with HSP90 inhibitors (AT13387, AUY-922) to assess protective and reparative effects.

Main Results:

• S1SP activated IKBα, STAT3, and AKT signaling pathways.
• S1SP exposure reduced the expression of critical endothelial junctional proteins, occludin and VE-cadherin.
• HSP90 inhibitors (AT13387, AUY-922) effectively prevented S1SP-induced endothelial barrier dysfunction and hyperpermeability.
• These inhibitors also mitigated S1SP-mediated signaling activation and restored VE-cadherin expression.

Conclusions:

• SARS-CoV-2 spike protein subunit 1 can directly induce endothelial injury and barrier dysfunction.
• HSP90 signaling plays a crucial role in mediating S1SP-induced endothelial damage.
• HSP90 inhibitors represent a promising therapeutic strategy for preserving endothelial function during SARS-CoV-2 infection.