Activation of cardiac adenylyl cyclase expression increases function of the failing ischemic heart in mice.
OBJECTIVE
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.
Lai
N Chin
NC
Department of Medicine, University of California San Diego, San Diego, California, USA.
Tang
Tong
T
Gao
Mei Hua
MH
Saito
Miho
M
Takahashi
Toshiyuki
T
Roth
David M
DM
Hammond
H Kirk
HK
D000262:Adenylyl Cyclases / Q000378:metabolism*; D000818:Animals; D017209:Apoptosis; D002311:Cardiomyopathy, Dilated / Q000150:complications / Q000201:enzymology / Q000503:physiopathology*; D003971:Diastole; D004789:Enzyme Activation; D006333:Heart Failure / Q000201:enzymology / Q000209:etiology / Q000401:mortality / Q000503:physiopathology*; D006352:Heart Ventricles / Q000503:physiopathology*; D051379:Mice; D023421:Models, Animal; D009203:Myocardial Infarction / Q000150:complications / Q000201:enzymology / Q000503:physiopathology*; D011943:Receptors, Adrenergic, beta; D044169:Receptors, Calcium-Sensing; D012307:Risk Factors; D015398:Signal Transduction; D013599:Systole; D019210:Troponin I
D011943:Receptors, Adrenergic, beta; D044169:Receptors, Calcium-Sensing; D019210:Troponin I; D000262:Adenylyl Cyclases