Cardiac-directed adenylyl cyclase expression improves heart function in murine cardiomyopathy

Background-We tested the hypothesis that increased cardiac myocyte adenylyl cyclase (AC) content increases cardiac function and response to catecholam ines 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 ca rdiac-directed G(q) expression. G(q) mice had dilated left ventricles, redu ced heart function, decreased cardiac responsiveness to catecholamine stimu lation, and impaired beta-adrenergic receptor (beta AR)-dependent and AC-de pendent cAMP production. G(q)/AC mice showed improved basal cardiac functio n in vivo (P = 0.01) and ex vivo (P < 0.0005), When stimulated through the beta AR, cardiac responsiveness was increased (P = 0.02), and cardiac myocy tes 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 beta AR stimulation.