Abstract 296: Loss of Trpc6 Function in Cardiomyocytes Improves Survival and Attenuates Progression of Cardiac Dysfunction After Mi

Abstract

Ischemic heart disease (IHD) commonly culminates in myocardial infarction (MI), which causes cardiac myocyte death and depressed cardiac pump function. Surviving myocytes can usually maintain pump function by increasing Ca 2+ influx and contractility. However, elevated intracellular Ca 2+ also can activate pathological hypertrophic signaling that promotes cardiac dysfunction and progression into heart failure. Ca 2+ influx through Canonical Transient Receptor Potential (TRPC) channels has been classified as a potential source of hypertrophic signaling. Specifically, TRPC6 gene expression and biological activity is significantly upregulated in cardiac myocytes after MI. Our aim was to determine if TRPC6 loss of function is cardioprotective in MI mouse model. We performed an MI study on cardiac specific dominant negative (dn) TRPC6 transgenic mice that express 3 mutated amino acids (L678A-W680A) in the pore region, which disables TRPC6 channel function. In the course of 6 weeks post MI, dnTRPC6 mice had significantly greater survival (69.2%) than wild-type (WT) mice (47.5%). Cardiac function at 2 weeks post MI was decreased to the same extent in WT and dnTRPC6 mice. Ejection fraction (EF) in WT group was 30.6% vs. 57.1% and in dnTRPC6 EF was 31% vs. 61% (MI vs. sham, respectively). The EF in dnTRPC6 mice 6 weeks post MI suggested attenuation of heart failure progression compared to WT mice (32.5% vs. 26.5%, *P=0.05). Mice in the WT group demonstrated significant elevation in end diastolic and end systolic volumes (EDV and ESV) 6 weeks post MI, while dnTRPC6 had reduced end diastolic and end systolic volumes (116μL vs. 88μL and 106μL vs. 76μL, WT vs. dnTRPC6, EDV and ESV, respectively. ***P<0.0001). Hypertrophy measures of heart weight to body weight ratio and heart weight to tibia length ratio were significantly reduced in dnTRPC6 mice 6 weeks post MI as opposed to WT mice (8.4 vs. 7.3 and 13.4 vs. 11.7, respectively *P<0.05). Hypertrophic markers of ANP, BNP and βMHC followed similar downregulation trend in the dnTRPC6 mice. In conclusion, loss of TRPC6 function slows the progression of cardiac dysfunction and cardiac remodeling in the post MI heart.