期刊
ONCOTARGET
卷 7, 期 25, 页码 37622-37635出版社
IMPACT JOURNALS LLC
DOI: 10.18632/oncotarget.9376
关键词
AMPK; atherosclerosis; GSK1016790A; shear stress; TRPV4
资金
- National Institutes of Health [R01HL109502, R01HL114570, R01HL08432]
- American Diabetes Association [7-12-BS-085]
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-alpha-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-alpha-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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