TRPV4 activates cytosolic phospholipase A2 via Ca2+ -dependent PKC/ERK1/2 signalling in controlling hypertensive contraction.

Abstract

Activation of TRPV4 (transient receptor potential vanilloid 4) has been reported to result in endothelium-dependent contraction in the aortae of hypertensive mice. This contraction involved increased cPLA2 (cytosolic phospholipase A2 ) activity. The mechanism by which TRPV4 regulates cPLA2 activity to induce contraction in hypertension, however, is unknown. Through measurements of arterial tension and protein level, we showed that high-salt diet induced hypertension increases activity of PKC (protein kinase C) and ERK1/2 (extracellular signal-regulated kinase 1/2). GSK1016790A, a TRPV4 agonist and ACh (acetylcholine) induced contractions were suppressed by Go6983, a PKC inhibitor and PD98059, an ERK1/2 inhibitor. TRPV4 activation increased activity of PKC and ERK1/2 in endothelial cells from hypertensive mice and this response was suppressed by HC067047, a TRPV4 inhibitor and BAPTA/AM, a Ca2+ chelator. PLA2 assay and western blotting showed that blocking of PKC or ERK1/2 inhibited TRPV4 or ACh-induced cPLA2 activity. Enzyme immunoassay showed that GSK1016790A or ACh triggered the release of PGF2α (prostaglandin F2α ) was reduced by inhibition of PKC or ERK1/2. These data further suggest Ca2+ /PKC/ERK1/2 axis as a novel mechanism for TRPV4 in the activation of cPLA2 in hypertension.