Disruption of type 5 adenylyl cyclase prevents β-adrenergic receptor cardiomyopathy: A novel approach to β-adrenergic receptor blockade

beta-Adrenergic receptor (beta-AR) blockade is widely used to treat heart failure, since the adverse effects of chronic beta-AR stimulation are central to the pathogenesis of this disease state. Transgenic (Tg) mice, where beta-AR signaling is chronically enhanced by overexpression of cardiac beta(2)-ARs, is a surrogate for this mechanism, since these mice develop cardiomyopathy as reflected by reduced left ventricular (LV) function, increased fibrosis, apoptosis, and myocyte hypertrophy. We hypothesized that disruption of type 5 adenylyl cyclase (AC5), which is in the beta-AR signaling pathway in the heart, but exerts only a minor beta-AR blocking effect, could prevent the cardiomyopathy in beta(2)-AR Tg mice without the negative effects of full beta-AR blockade. Accordingly, we mated beta(2)-AR Tg mice with AC5 knockout (KO) mice. The beta(2)-AR Tg x AC5 KO bigenic mice prevented the cardiomyopathy as reflected by improved LV ejection fraction, reduced apoptosis, fibrosis, and myocyte size and preserved exercise capacity. The rescue was not simply due to a beta-blocking effect of AC5 KO, since neither baseline LV function nor the response to isoproterenol was diminished substantially compared with the negative inotropic effects of beta-blockade. However, AC5 disruption in beta(2)-AR Tg activates the antioxidant, manganese superoxide dismutase, an important mechanism protecting the heart from cardiomyopathy. These results indicate that disruption of AC5 prevents the cardiomyopathy induced by chronically enhanced beta-AR signaling in mice with overexpressed beta(2)-AR, potentially by enhancing resistance to oxidative stress and apoptosis, suggesting a novel, alternative approach to beta-AR blockade.