A novel TRPV4-specific agonist inhibits monocyte adhesion and atherosclerosis

// Suowen Xu 1 , Bin Liu 1 , Meimei Yin 1 , Marina Koroleva 1 , Michael Mastrangelo 1 , Sara Ture 1 , Craig N. Morrell 1 , David X. Zhang 2 , Edward A. Fisher 3 and Zheng Gen Jin 1 1 Aab Cardiovascular Research Institute and Department of Medicine, University of Rochester School of Medicine and Dentistry, Rochester, NY, USA 2 Department of Medicine, Medical College of Wisconsin, Milwaukee, WI, USA 3 Department of Medicine, Division of Cardiology, and The Marc and Ruti Bell Program in Vascular Biology, New York University School of Medicine, New York, NY, USA Correspondence to: Zheng Gen Jin, email: // Keywords : AMPK, atherosclerosis, GSK1016790A, shear stress, TRPV4 Received : December 29, 2015 Accepted : April 29, 2016 Published : May 14, 2016 Abstract TRPV4 ion channel mediates vascular mechanosensitivity and vasodilation. Here, we sought to explore whether non-mechanical activation of TRPV4 could limit vascular inflammation and atherosclerosis. We found that GSK1016790A, a potent and specific small-molecule agonist of TRPV4, induces the phosphorylation and activation of eNOS partially through the AMPK pathway. Moreover, GSK1016790A inhibited TNF-α-induced monocyte adhesion to human endothelial cells. Mice given GSK1016790A showed increased phosphorylation of eNOS and AMPK in the aorta and decreased leukocyte adhesion to TNF-α-inflamed endothelium. Importantly, oral administration of GSK1016790A reduced atherosclerotic plaque formation in ApoE deficient mice fed a Western-type diet. Together, the present study suggests that pharmacological activation of TRPV4 may serve as a potential therapeutic approach to treat atherosclerosis.