Cardiac-Directed Adenylyl Cyclase Expression Improves Heart Function in Murine Cardiomyopathy

Abstract

Background —We tested the hypothesis that increased cardiac myocyte adenylyl cyclase (AC) content increases cardiac function and response to catecholamines in cardiomyopathy. Methods and Results —Transgenic mice with cardiac-directed expression of AC type VI (AC VI ) were crossbred with mice with cardiomyopathy induced by cardiac-directed G q expression. G q mice had dilated left ventricles, reduced heart function, decreased cardiac responsiveness to catecholamine stimulation, and impaired β-adrenergic receptor (βAR)–dependent and AC-dependent cAMP production. G q /AC mice showed improved basal cardiac function in vivo ( P =0.01) and ex vivo ( P <0.0005). When stimulated through the βAR, cardiac responsiveness was increased ( P =0.02), and cardiac myocytes showed increased cAMP production in response to isoproterenol ( P =0.03) and forskolin ( P <0.0001). Conclusions —Increasing myocardial AC VI content in cardiomyopathy restores cAMP-generating capacity and improves cardiac function and responsiveness to βAR stimulation.