Abstract 5936: Inhibition of Type 5 Adenylyl Cyclase Rescues Cardiomyopathy Induced by Overexpressed beta2-Adrenergic Receptors in the Heart
Chronic beta-adrenergic receptor (beta-AR) stimulation is deleterious and is involved in the pathogenesis of heart failure (HF). Transgenic (Tg) mice, where beta-AR signaling is chronically enhanced by overexpression of cardiac beta2-AR, develop cardiomyopathy at the age of 11–15 months, as reflected by reduced left ventricular (LV) function (47±2% vs. 66±1%, p<0.05), a 10- fold increase in fibrosis, increased apoptosis (3.8±0.6% vs. 0.2±0.1%, p<0.05), and increased myocyte hypertrophy, as reflected by cell cross sectional area (444±34 vs. 920±51 microm2, p<0.05). Conversely, inhibition of type 5 adenylyl cyclase (AC5), which plays a pivotal role in beta-AR signaling, increases longevity and protects against aging-induced cardiomyopathy and stress, as we have reported previously. We hypothesized that inhibition of AC5 could rescue the cardiomyopathy in these Tg mice. Accordingly, we mated beta2-AR Tg mice with AC5 knockout (KO) mice. In beta2-AR Tg x AC5 KO bigenic mice (n=14; 11–15 months old) exhibited rescued LV function as reflected by LVEF (73±2% vs. 47±2% p<0.05), reduced apoptosis measured by TUNEL (0.11±0.01% vs 3.81±0.56%, p<0.05) and the level of cleaved caspase-3 (50%), reduced fibrosis (0.87±0.2% vs 5.23±0.4%, p<0.05), and reduced myocyte size (587±28 vs 920±51 microm2, p<0.05). The rescue was not simply due to a beta blocking effect of AC5 since acute ISO challenge, 0.05 microg/kg/min, increased LVEF similarly in WT (67 to 76%) and in bigenic mice (71 to 78%). Accordingly, we examined the role of oxidative stress in neonatal myocytes. Compared with WT, myocytes isolated from AC5 KO showed a 40% increase, whereas myocytes from beta2-AR Tg showed a 60% decrease, in cell viability in response to H2O2. Beta2-AR Tg myocytes also increased ROS production by 50% compared with WT myocytes using CM-H2DCFDA fluorescent assay. The activity of the antioxidant, MnSOD, increased in AC5 KO (30%) and beta2-AR Tg x AC5 KO bigenic mice (25%) compared to beta2-AR Tg mice (p<0.05). These results indicate that inhibition of AC5 rescues the cardiomyopathy induced by chronically enhanced beta-AR signaling in mice with overexpressed beta2-AR, potentially by enhancing resistance to oxidative stress and apoptosis.