Increased cardiac adenylyl cyclase expression is associated with increased survival after myocardial infarction

• Published in: Circulation (New York, N.Y.) N.Y.), 2006-08, Vol.114 (5), p.388-396
• Main Authors: TAKAHASHI, Toshiyuki, TONG TANG, LAI, N. Chin, ROTH, David M, REBOLLEDO, Brian, SAITO, Miho, LEW, Wilbur Y. W, CLOPTON, Paul, HAMMOND, H. Kirk
• Format: Article
• Language: English
• Subjects: Adenylyl Cyclases - analysis; Adenylyl Cyclases - genetics; Adenylyl Cyclases - physiology; Adrenergic beta-Antagonists - pharmacology; Animals; Apoptosis - physiology; Biological and medical sciences; Blood and lymphatic vessels; Blood coagulation. Blood cells; Calcium - metabolism; Cardiology. Vascular system; Coronary heart disease; Cyclic AMP - analysis; Cyclic AMP - physiology; Diseases of the peripheral vessels. Diseases of the vena cava. Miscellaneous; Female; Fundamental and applied biological sciences. Psychology; Gene Expression Regulation, Enzymologic - physiology; GTP-Binding Proteins - analysis; GTP-Binding Proteins - genetics; GTP-Binding Proteins - physiology; Heart; Heart Ventricles - chemistry; Heart Ventricles - pathology; Heart Ventricles - physiopathology; Hemodynamics - physiology; Male; Medical sciences; Mice; Mice, Transgenic; Molecular and cellular biology; Myocardial Contraction - physiology; Myocardial Infarction - mortality; Myocardial Infarction - pathology; Myocardial Infarction - physiopathology; Platelet; Propranolol - pharmacology; Receptors, Adrenergic, beta - analysis; Receptors, Adrenergic, beta - drug effects; Receptors, Adrenergic, beta - genetics; Receptors, Adrenergic, beta - physiology; Survival Rate; Ventricular Remodeling - physiology
• ISSN: 0009-7322; 1524-4539
• DOI: 10.1161/CIRCULATIONAHA.106.632513

Cardiac-directed expression of adenylyl cyclase type VI (AC(VI)) in mice results in structurally normal hearts with normal basal heart rate and function but increased responses to catecholamine stimulation. We tested the hypothesis that increased left ventricular (LV) AC(VI) content would increase mortality after acute myocardial infarction (MI). Transgenic mice with cardiac-directed AC(VI) expression and their transgene-negative littermates (control) underwent coronary ligation, and survival, infarct size, and LV size and function were assessed 1 to 7 days after MI. Mice with increased AC(VI) expression had increased survival (control 41%, AC(VI) 74%; P = 0.004). Infarct size and myocardial apoptotic rates were similar in AC(VI) and control mice; however, AC(VI) mice had less LV dilation (P < 0.001) and increased ejection fractions (P < 0.03). Three days after MI, studies in isolated perfused hearts showed that basal LV +dP/dt was similar, but graded dobutamine infusion was associated with a more robust LV contractile response in AC(VI) mice (P < 0.05). Increased LV function was associated with increases in cAMP generation (P = 0.0002), phospholamban phosphorylation (P < 0.04), sarcoplasmic reticulum Ca2+-ATPase (SERCA2a) affinity for calcium (P < 0.015), and reduced AV block (P = 0.04). In acute MI, increased cardiac AC(VI) content attenuates adverse LV remodeling, preserves LV contractile function, and reduces mortality.