Activation of Cardiac Adenylyl Cyclase Expression Increases Function of the Failing Ischemic Heart in Mice

ObjectivesThis study sought to evaluate whether increased left ventricular (LV) adenylyl cyclase VI (ACVI) expression, at a time when severe congestive heart failure (CHF) was present, would increase function of the actively failing heart.BackgroundIncreased LV ACVI content markedly reduces mortality and increases LV function after acute myocardial infarction (MI) in mice. However, the effects of increased cardiac ACVI content in the setting of severe heart failure caused by ischemic cardiomyopathy are unknown.MethodsMice with cardiac-directed and regulated expression of ACVI underwent coronary artery ligation to induce severe CHF 5 weeks later. ACVI expression was then activated in 1 group (AC-On) but not the other (AC-Off). Multiple measures of LV systolic and diastolic function were obtained 5 weeks later, and LV samples were assessed for alterations in calcium and beta-adrenergic receptor signaling, apoptosis, and cardiac troponin I phosphorylation.ResultsThe LV systolic and diastolic function was increased 5 weeks after activation of ACVI expression. Improved LV function was associated with normalization of cardiac troponin I phosphorylation and reduced apoptosis.ConclusionsActivation of cardiac ACVI expression in mice with ischemic cardiomyopathy and severe CHF improves function of the failing heart.