title: A novel TRPV4-specific agonist inhibits monocyte adhesion and atherosclerosis.
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.
authors.affiliation: Aab Cardiovascular Research Institute and Department of Medicine, University of Rochester School of Medicine and Dentistry, Rochester, NY, USA.
authors.forename: Suowen
authors.initials: S
authors.lastname: Xu
authors.affiliation: Aab Cardiovascular Research Institute and Department of Medicine, University of Rochester School of Medicine and Dentistry, Rochester, NY, USA.
authors.forename: Bin
authors.initials: B
authors.lastname: Liu
authors.affiliation: Aab Cardiovascular Research Institute and Department of Medicine, University of Rochester School of Medicine and Dentistry, Rochester, NY, USA.
authors.forename: Meimei
authors.initials: M
authors.lastname: Yin
authors.affiliation: Aab Cardiovascular Research Institute and Department of Medicine, University of Rochester School of Medicine and Dentistry, Rochester, NY, USA.
authors.forename: Marina
authors.initials: M
authors.lastname: Koroleva
authors.affiliation: Aab Cardiovascular Research Institute and Department of Medicine, University of Rochester School of Medicine and Dentistry, Rochester, NY, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Mastrangelo
authors.affiliation: Aab Cardiovascular Research Institute and Department of Medicine, University of Rochester School of Medicine and Dentistry, Rochester, NY, USA.
authors.forename: Sara
authors.initials: S
authors.lastname: Ture
authors.affiliation: Aab Cardiovascular Research Institute and Department of Medicine, University of Rochester School of Medicine and Dentistry, Rochester, NY, USA.
authors.forename: Craig N
authors.initials: CN
authors.lastname: Morrell
authors.affiliation: Department of Medicine, Medical College of Wisconsin, Milwaukee, WI, USA.
authors.forename: David X
authors.initials: DX
authors.lastname: Zhang
authors.affiliation: 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.
authors.forename: Edward A
authors.initials: EA
authors.lastname: Fisher
authors.affiliation: Aab Cardiovascular Research Institute and Department of Medicine, University of Rochester School of Medicine and Dentistry, Rochester, NY, USA.
authors.forename: Zheng Gen
authors.initials: ZG
authors.lastname: Jin
mesh_terms: D000818:Animals; D050197:Atherosclerosis / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D002448:Cell Adhesion / Q000187:drug effects; D055785:Gene Knockdown Techniques; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D007930:Leucine / Q000031:analogs & derivatives / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009000:Monocytes / Q000187:drug effects* / Q000473:pathology; D013449:Sulfonamides / Q000494:pharmacology; D050916:TRPV Cation Channels / Q000819:agonists* / Q000235:genetics; D020298:U937 Cells
chemical_list: C530602:N-(1-((4-(2-(((2,4-dichlorophenyl)sulfonyl)amino)-3-hydroxypropanoyl)-1-piperazinyl)carbonyl)-3-methylbutyl)-1-benzothiophene-2-carboxamide; D013449:Sulfonamides; D050916:TRPV Cation Channels; C416986:TRPV4 protein, human; C486576:Trpv4 protein, mouse; D007930:Leucine
keywords: AMPK; GSK1016790A; TRPV4; atherosclerosis; shear stress