Reduction of Adenylyl Cyclase Type 5 Protects Obesity Induced Cardiomyopathy

Abstract

Since mice with adenylyl cyclase type 5 (AC5) gene disruption eat more than wild type (WT), but weigh less, the goal of this study was to determine if these mice are protected against obesity and the cardiomyopathy induced by a high fat diet (HFD) for 100 days. AC5KO mice gained less weight/kcal consumed than wild type (WT) on HFD, p<0.05, and insulin resistance and glucose tolerance were improved compared to WT on HFD. The HFD induced cardiomyopathy was characterized by reduced, p<0.05, left ventricular (LV) ejection fraction (EF) (53±2.4%) compared with normal diet (ND) (69±2.9%), whereas the reduction in LVEF was less, p<0.05, in AC5KO on HFD (61±3.0%). The cardiomyopathy was also characterized by increased myocardial fibrosis, assessed by picric Sirius red staining, and increased apoptosis, expressed as TUNEL positive cells per mm2. The AC5KO exhibited reduced fibrosis (1.2±0.1%) compared with WT (1.7±0.1%) on HFD, p<0.05, as well as reduced apoptosis (0.5±0.04) compared with WT (0.9±0.1) on HFD, p<0.05. We also examined the effects of pharmacologic inhibition of AC5 with AraAde, an antiviral compound that has AC5 inhibitory effects; weight gain, glucose tolerance, insulin resistance, LV function and fibrosis were all improved compared to vehicle treated mice on HFD. Thus inhibition of AC5 protects against obesity and the cardiomyopathy it induces.