An Orally Active TRPV4 Channel Blocker Prevents and Resolves Pulmonary Edema Induced by Heart Failure

作者：Thorneloe Kevin S^*; Cheung Mui; Bao Weike; Alsaid Hasan; Lenhard Stephen; Jian Ming Yuan; Costell Melissa; Maniscalco Hauk Kristeen; Krawiec John A; Olzinski Alan; Gordon Earl; Lozinskaya Irina; Elefante Lou; Qin Pu; Matasic Daniel S; James Chris; Tunstead James; Donovan Brian; Kallal Lorena; Waszkiewicz Anna; Vaidya Kalindi; Davenport Elizabeth A; Larkin Jonathan; Burgert Mark; Casillas Linda N; Marquis Robert W; Ye Guosen; Eidam Hilary S; Goodman Krista B

来源：Science Translational Medicine, 2012, 4(159): 159ra148.

DOI：10.1126/scitranslmed.3004276

Pulmonary edema resulting from high pulmonary venous pressure (PVP) is a major cause of morbidity and mortality in heart failure (HF) patients, but current treatment options demonstrate substantial limitations. Recent evidence from rodent lungs suggests that PVP-induced edema is driven by activation of pulmonary capillary endothelial transient receptor potential vanilloid 4 (TRPV4) channels. To examine the therapeutic potential of this mechanism, we evaluated TRPV4 expression in human congestive HF lungs and developed small-molecule TRPV4 channel blockers for testing in animal models of HF. TRPV4 immunolabeling of human lung sections demonstrated expression of TRPV4 in the pulmonary vasculature that was enhanced in sections from HF patients compared to controls. GSK2193874 was identified as a selective, orally active TRPV4 blocker that inhibits Ca2+ influx through recombinant TRPV4 channels and native endothelial TRPV4 currents. In isolated rodent and canine lungs, TRPV4 blockade prevented the increased vascular permeability and resultant pulmonary edema associated with elevated PVP. Furthermore, in both acute and chronic HF models, GSK2193874 pretreatment inhibited the formation of pulmonary edema and enhanced arterial oxygenation. Finally, GSK2193874 treatment resolved pulmonary edema already established by myocardial infarction in mice. These findings identify a crucial role for TRPV4 in the formation of HF-induced pulmonary edema and suggest that TRPV4 blockade is a potential therapeutic strategy for HF patients.

• 出版日期2012-11-7