Heat Shock Protein 90 Inhibitors Protect and Restore Pulmonary Endothelial Barrier Function
Heat Shock Protein 90 Inhibitors Protect and Restore Pulmonary Endothelial Barrier Function
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DOI：
10.1165/rcmb.2007-0324oc
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发表时间：
2008-11-01
影响因子：
6.4
通讯作者：
Catravas, John D.
中科院分区：
文献类型：
--
作者：
Antonov, Alexander;Snead, Connie;Catravas, John D.
热休克蛋白90 （hsp90）抑制剂灭活和/或降解多种客户蛋白，包括许多与炎症有关的蛋白。血管通透性增加是急性肺损伤（ALI）和急性呼吸窘迫综合征（ARDS）的标志。因此，我们验证了hsp90抑制剂可能阻止和/或恢复内皮细胞（EC）损伤后通透性的假设。融合牛肺动脉内皮细胞（BPAEC）单层暴露于tgf - β 1、凝血酶、细菌脂多糖（LPS）或血管内皮生长因子（VEGF）下，可以增加BPAEC的通透性，这可以通过降低经内皮电阻（TER）来证实。用hsp90抑制剂治疗损伤内皮后，BPAEC的TER完全恢复。同样，用hsp90抑制剂对BPAEC进行预孵育可以防止凝血酶、LPS、VEGF或tgf - β 1暴露引起的TER下降。此外，hsp90抑制剂可恢复PMA或诺可达唑诱导的高通透性后的EC屏障功能。hsp90抑制剂的这些作用与恢复tgf - β 1或诺可达唑诱导的EC连接处VE-cadherin和P-catenin表达的减少有关。hsp90抑制剂对tgf - β 1诱导的高通透性的保护作用严重依赖于f -肌动蛋白细胞骨架的保存，并与激动剂诱导的肌球蛋白轻链（MLC）和肌球蛋白磷酸酶靶亚基1 （MYPT1）磷酸化、f -肌动蛋白应激纤维形成、微管分解、hsp27磷酸化增加以及hsp90与hsp27的关联有关，但与p38MAPK活性无关。我们得出结论，hsp90抑制剂对BPAEC发挥屏障保护作用，至少部分是通过抑制hsp27介导的，激动剂诱导的细胞骨架重排，因此可能对ALI， ARDS和其他肺部炎症性疾病具有有用的治疗价值。
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-beta 1, 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-beta 1. 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-beta 1- or nocodazole-induced decrease in VE-cadherin and P-catenin expression at EC junctions. The protective effect of hsp90 inhibitors on TGF-beta 1-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.