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A novel TRPV4-specific agonist inhibits monocyte adhesion and atherosclerosis. Oncotarget 2016 Jun 21;7(25):37622-37635

Date

10/23/2016

Pubmed ID

27191895

Pubmed Central ID

PMC5122337

DOI

10.18632/oncotarget.9376

Scopus ID

2-s2.0-84978176831   28 Citations

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.

Author List

Xu S, Liu B, Yin M, Koroleva M, Mastrangelo M, Ture S, Morrell CN, Zhang DX, Fisher EA, Jin ZG

Author

David X. Zhang MD, PhD Associate Professor in the Medicine department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

Animals
Atherosclerosis
Cell Adhesion
Gene Knockdown Techniques
Human Umbilical Vein Endothelial Cells
Humans
Leucine
Male
Mice
Mice, Inbred C57BL
Monocytes
Sulfonamides
TRPV Cation Channels
U937 Cells
jenkins-FCD Prod-482 91ad8a360b6da540234915ea01ff80e38bfdb40a