Abstract 12163: Loss and Gain of Function Analysis of Transient Receptor Potential Vanilloid 2 Reveals Novel Roles in Baseline Cardiac Function, Contractility, Lusitropy and Hypertrophy
Introduction: We have previously shown that transient receptor potential vanilloid 2 (TRPV2) is present in the murine and human heart and when agonized induces a positive inotropic response. This study investigated the mechanism of action of this channel as it pertains to cardiac contractility and development of hypertrophy with wild type (WT) and TRPV2-/- mice (KO).
Methods and Results: Cell mechanics and intracellular calcium measurements. Cardiac myocytes were isolated and paced. We found that TRPV2 abrogation attenuates Ca2+ kinetics, decreases SR Ca2+ load and causes a decrease in contractility and relaxation in isolated cardiomyocytes(FS(%): 13.3±0.2 vs. 9.2±0.2; p≤0.05).
Cardiac and vascular function in-vivo: Measurements of cardiac function and vascular tone were performed in WT and KO mice via echocardiography and invasively. Probenecid, a TRPV2 agonist, was administered IV in the invasive cohort. We found that TRPV2 abrogation causes a decrease in systolic and diastolic function independent of preload and afterload. (+dp/dt: 8480.5±524.5 vs. 6722±457.9 and -dp/dt:9618.7±1544.4 vs. 7024±438.8; p≤0.05 for both). Probenecid improved systolic and diastolic function in WT but not KO.
Response to exercise: WT and KO mice were subjected to strenuous exercise. The KO mice were found to have significantly more interruptions to the exercise associated with increasing speeds (3.4±1.8 vs. 0.4±0.1 at 16 mpm;p≤0.05).
Ventricular response to increased afterload: WT and KO mice were subjected to pressure overload via TAC and followed echocardiographically for 8 weeks. We found that TRPV2 abrogation is associated with decreased left ventricular hypertrophy after TAC. (HW(g):0.21±0.009 vs. 0.17±0.009;p=0.05).
Conclusions: We have shown that TRPV2 modulates contractility independent of any vascular effects and directly through modulation of SR Ca2+ load. The stimulation of this channel results in a positive inotropic and lusitropic response while its abrogation is associated with decreased exercise capacity and development of hypertrophy. These findings, if confirmed in translational and human studies, have significant implication in the management of patients with systolic and diastolic heart failure.
- © 2013 by American Heart Association, Inc.