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

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Objectives

This 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.

Background

Increased 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.

Methods

Mice 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.

Results

The 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.

Conclusions

Activation of cardiac ACVI 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

Cited by (0)

This work was supported by National Institutes of Health grants 5P01HL066941, HL088426, and HL081741 (Dr. Hammond), Merit Review Awards from the Department of Veteran’s Affairs (Drs. Roth and Hammond), a Grant-in-Aid from the American Heart Association Western States Affiliate (Dr. Gao), and a fellowship from the Banyu Life Science Foundation International (Dr. Takahashi). Drs. Lai and Tang contributed equally to this work. Lynne Warner Stevenson, MD, served as Guest Editor for this article.