Abstract 21096: Regulation of Cardiac Hypertrophy by the Calcium Channel TRPV1
TRPV1 is a calcium channel activated by endocannabinoids, and low pH. It is widely expressed in neuronal tissue, lung, kidney, spleen, heart, neutrophils, myocytes, and mast cells. Yeast two-hybrid and confirmatory immunoprecipitation (IP) showed TRPV1 interacting with the atrial natriuretic peptide (ANP) receptor (NPR1). We hypothesized that this interaction regulates TRPV1 activation. NPR1 is a guanylate cyclase, converting GMP to cGMP. PKG is the major target for cGMP. TRPV1 is enriched in anti-phospho PKG immunoprecipitations after cellular treatment with ANP, showing that TRPV1 is a PKG substrate. Pre-treatment with DT2, a PKG inhibitor, facilitates TRPV1 activation, but ANP treatment inhibits activation, shown by NFAT protein reporter assay. This suggests that physiologically ANP binding to NPR1 mediates PKG phosphorylation to suppress TRPV1 activation. ANP is released by stressed cardiac myocytes in response to the increased workload associated with cardiac hypertrophy. We hypothesize that ANP regulates TRPV1 activation in this disease. We tested if Trpv1 knockout would suppress the rate of hypertrophy in a surgical model for pressure overload cardiac hypertrophy; transverse aortic constriction (TAC). Echocardiography was used to measure the internal dimensions of the heart post TAC/sham treatment. The data show a significant increase in the rate of left ventricle (LV) internal diameter, in WT mice (n=17) as compared to Trpv1−/− mice (n=15) (P<0.05). Sham controls did not differ significantly. LV function (% fractional shortening) appears to be preserved in Trpv1−/− mice WT (n=17), Trpv1−/− (n=15), while controls showed no significant difference. Six weeks post TAC/sham, hearts were collected for analysis of hypertrophy markers. Data show less interstitial collagen deposition, and decreased transcript&protein levels for multiple markers of hypertrophy and tissue remodeling proteins. Thus Trpv1 knockout suppresses the rate of hypertrophy, preserving heart function, with less fibrosis and tissue remodeling, in response to modeled pressure overload cardiac hypertrophy. The data generated here identify TRPV1 as a putative target for the clinical treatment of cardiac hypertrophy.
- © 2010 by American Heart Association, Inc.