Abstract 242: A Novel Transient Receptor Potential Ion Channel Vanilloid 4 Agonist Inhibits Monocytes Adhesion and Atherosclerosis via eNOS Activation

Endothelial nitric oxide (NO) synthase (eNOS/NOS3)-derived NO represents an important vasculoprotective molecule in the cardiovascular system. The transient receptor potential ion channel vanilloid subtype 4 (TRPV4) mediates vascular mechanosensitivity, in part through an increase in blood flow-mediated NO production and endothelium-dependent relaxation. Here, we hypothesized that non-mechanical TRPV4 activation can mimic laminar flow-induced signaling and thereby limits monocyte adhesion and atherosclerosis. We observed that GSK1016790A, a novel, potent and specific agonist of TRPV4, mimics laminar flow, thereby inducing robust phosphorylation (Ser1177) of eNOS in a TRPV4 and calcium-dependent manner. Mechanistically, GSK1016790A induced eNOS phosphorylation, NO production and vasorelaxation via calcium/calmodulin-dependent kinase kinase (CaMKK)/AMP-activated protein kinase (AMPK) pathway. In functional experiments, GSK1016790A inhibited TNFα-induced monocytes adhesion to human endothelial cells by inhib...