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

N. Chin Lai, PhD^_*,, Tong Tang, PhD^_*,, Mei Hua Gao, PhD^_*,, Miho Saito, MD^_*, Toshiyuki Takahashi, MD, PhD^_*, David M. Roth, MD, PhD^, and H. Kirk Hammond, MD^_*,,_*

^_* Department of Medicine, University of California San Diego, San Diego, California
VA San Diego Healthcare System, University of California San Diego, San Diego, California
Department of Anesthesiology, University of California San Diego, San Diego, California.

Manuscript received September 4, 2007; revised manuscript received January 7, 2008, accepted January 10, 2008.

^_* Reprint requests and correspondence: Dr. H. Kirk Hammond, VA San Diego Healthcare System (111A), 3350 La Jolla Village Drive, San Diego, California 92161. (Email: khammond{at}ucsd.edu).

Objectives: This study sought to evaluate whether increased left ventricular (LV) adenylyl cyclase VI (AC_VI) expression, at a time when severe congestive heart failure (CHF) was present, would increase function of the actively failing heart.

Background: Increased LV AC_VI content markedly reduces mortality and increases LV function after acute myocardial infarction (MI) in mice. However, the effects of increased cardiac AC_VI content in the setting of severe heart failure caused by ischemic cardiomyopathy are unknown.

Methods: Mice with cardiac-directed and regulated expression of AC_VI underwent coronary artery ligation to induce severe CHF 5 weeks later. AC_VI 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.

Results: The LV systolic and diastolic function was increased 5 weeks after activation of AC_VI expression. Improved LV function was associated with normalization of cardiac troponin I phosphorylation and reduced apoptosis.

Conclusions: Activation of cardiac AC_VI expression in mice with ischemic cardiomyopathy and severe CHF improves function of the failing heart.

Abbreviations and Acronyms   ACVI = adenylyl cyclase VI   cAMP = cyclic adenosine monophosphate   CHF = congestive heart failure   +dP/dt = pressure development   EF = ejection fraction   ESP = end-systolic pressure   ESPVR = end-systolic pressure–volume relationship   FAC = fractional area change   LV = left ventricular   MI = myocardial infarction   MMP = matrix metalloproteinase   PKA = protein kinase A   PP1 = protein phosphatases 1   PP2A = protein phosphatases 2A   RLU = relative light units   SR = sarcoplasmic reticulum