Heat shock protein 90 inhibitors attenuate LPS-induced endothelial hyperpermeability.
Endothelial hyperperme ability leading to vascular leak is an important consequence of sepsis and sepsis-induced lung injury. We previously reported that heat shock protein (hsp) 90 inhibitor pretreatment improved pulmonary barrier dysfunction in a murine model of sepsis-induced lung injury. We now examine the effects of hsp90 inhibitors on LPS-mediated endothelial hyperpermeability, as reflected in changes in transendothelial electrical resistance (TER) of bovine pulmonary arterial endothelial cells (BPAEC). Vehicle-pretreated cells exposed to endotoxin exhibited a concentration-dependent decrease in TER, activation of pp60(Src), phosphorylation of the focal adhesion protein paxillin, and reduced expression of the adherens junction proteins, vascular endothelial (VE)-cadherin and beta-catenin. Pretreatment with the hsp90 inhibitor, radicicol, prevented the decrease in TER, maintained VE-cadherin and beta-catenin expression, and inhibited activation of pp60(Src) and phosphorylation of paxillin. Similarly, when BPAEC hyperpermeability was induced by endotoxin-activated neutrophils, pretreatment of neutrophils and/or endothelial cells with radicicol protected against the activated neutrophil-induced decrease in TER. Increased paxillin phosphorylation and decreased expression of beta-catenin and VE-cadherin were also observed in mouse lungs 12 h after intraperitoneal endotoxin and attenuated in mice pretreated with radicicol. These results suggest that hsp90 plays an important role in sepsis-associated endothelial barrier dysfunction.
Chatterjee
Anuran
A
Program in Pulmonary Vascular Disease, Vascular Biology Center, Medical College of Georgia, Augusta, GA 30912-2500, USA.
Snead
Connie
C
Yetik-Anacak
Gunay
G
Antonova
Galina
G
Zeng
Jingmin
J
Catravas
John D
JD
D000818:Animals; D002417:Cattle; D002463:Cell Membrane Permeability / Q000187:drug effects*; D002478:Cells, Cultured; D004553:Electric Conductivity; D017097:Electric Impedance; D004594:Electrophysiology; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors*; D008070:Lipopolysaccharides / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D011651:Pulmonary Artery / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D018805:Sepsis / Q000517:prevention & control
D018841:HSP90 Heat-Shock Proteins; D008070:Lipopolysaccharides