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Heat Shock Protein 90 Inhibitors Protect and Restore Pulmonary Endothelial Barrier Function

¹ Pulmonary Vascular Disease Program, Vascular Biology Center, ² Division of Pulmonary and Critical Care Medicine, Department of Medicine, and ³ Department of Pharmacology and Toxicology, Medical College of Georgia, Augusta, Georgia

Correspondence and requests for reprints should be addressed to John D. Catravas, Ph.D., Vascular Biology Center, Medical College of Georgia, Augusta, GA 30912-2500. E-mail: jcatrava{at}mcg.edu

Heat shock protein 90 (hsp90) inhibitors inactivate and/or degrade various client proteins, including many involved in inflammation. Increased vascular permeability is a hallmark of acute lung injury (ALI) and acute respiratory distress syndrome (ARDS). Thus, we tested the hypothesis that hsp90 inhibitors may prevent and/or restore endothelial cell (EC) permeability after injury. Exposure of confluent bovine pulmonary arterial endothelial cell (BPAEC) monolayer to TGF-β1, thrombin, bacterial lipopolysaccharide (LPS), or vascular endothelial growth factor (VEGF) increased BPAEC permeability, as revealed by decreased transendothelial electrical resistance (TER). Treatment of injured endothelium with hsp90 inhibitors completely restored TER of BPAEC. Similarly, preincubation of BPAEC with hsp90 inhibitors prevented the decline in TER induced by the exposure to thrombin, LPS, VEGF, or TGF-β1. In addition, hsp90 inhibitors restored the EC barrier function after PMA or nocodazole-induced hyperpermeability. These effects of the hsp90 inhibitors were associated with the restoration of TGF-β1– or nocodazole-induced decrease in VE-cadherin and β-catenin expression at EC junctions. The protective effect of hsp90 inhibitors on TGF-β1–induced hyperpermeability was critically dependent upon preservation of F-actin cytoskeleton and was associated with the inhibition of agonist-induced myosin light chain (MLC) and myosin phosphatase target subunit 1 (MYPT1) phosphorylation, F-actin stress fibers formation, microtubule disassembly, increase in hsp27 phosphorylation, and association of hsp90 with hsp27, but independent of p38MAPK activity. We conclude that hsp90 inhibitors exert barrier protective effects on BPAEC, at least in part, via inhibition of hsp27-mediated, agonist-induced cytoskeletal rearrangement, and therefore may have useful therapeutic value in ALI, ARDS, and other pulmonary inflammatory disease.

Key Words: endothelial permeability • TGF-β1 • hsp27 • 17-AAG • MYPT1

CLINICAL RELEVANCE The finding that hsp90 inhibitors, including 17AAG (which is currently undergoing clinical trials related to cancer), prevent and restore endothelial cell permeability induced by several major inflammatory mediators may lead to a new intervention to control inflammation and endothelial barrier function in patients with acute lung injury.