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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-?-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-?-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.

SUBMITTER: Xu S 

PROVIDER: S-EPMC5122337 | biostudies-literature | 2016 Jun

REPOSITORIES: biostudies-literature

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A novel TRPV4-specific agonist inhibits monocyte adhesion and atherosclerosis.

Xu Suowen S   Liu Bin B   Yin Meimei M   Koroleva Marina M   Mastrangelo Michael M   Ture Sara S   Morrell Craig N CN   Zhang David X DX   Fisher Edward A EA   Jin Zheng Gen ZG  

Oncotarget 20160601 25


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 p  ...[more]

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