A novel TRPV4-specific agonist inhibits monocyte adhesion and atherosclerosis
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Suowen Xu1, Bin Liu1, Meimei Yin1, Marina Koroleva1, Michael Mastrangelo1, Sara Ture1, Craig N. Morrell1, David X. Zhang2, Edward A. Fisher3 and Zheng Gen Jin1
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
Zheng Gen Jin, email:
Keywords: AMPK, atherosclerosis, GSK1016790A, shear stress, TRPV4
Received: December 29, 2015 Accepted: April 29, 2016 Published: May 14, 2016
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.
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