Adenylyl Cyclase 6 Improves Calcium Uptake and Left Ventricular Function in Aged Hearts

• Published in: Journal of the American College of Cardiology 2011-05, Vol.57 (18), p.1846-1855
• Main Authors: Tang, Tong, PhD, Hammond, H. Kirk, MD, Firth, Amy, PhD, Yang, Yuan, MD, Gao, Mei Hua, PhD, Yuan, Jason X.-J., MD, PhD, Lai, N. Chin, PhD
• Format: Article
• Language: English
• Subjects: adenylyl cyclase; Adenylyl Cyclases - physiology; Adrenergic beta-Agonists - pharmacology; Age; Aging; Aging - physiology; Animals; Biological and medical sciences; Calcium; Calcium - metabolism; calcium uptake; Calcium-Binding Proteins - metabolism; cardiac aging; Cardiology; Cardiology. Vascular system; Cardiovascular; Cyclic AMP - metabolism; Cyclic AMP-Dependent Protein Kinases - metabolism; Echocardiography; extracellular matrix remodeling; Gene expression; Heart; Heart attacks; Hypotheses; Internal Medicine; Isoproterenol - pharmacology; Kinases; Laboratory animals; left ventricular function; Medical sciences; Mice; Mortality; Myocardial Contraction - physiology; Myocytes, Cardiac - metabolism; Phosphorylation; Physiology; Protein Synthesis Inhibitors - pharmacology; Rodents; Sarcoplasmic Reticulum - metabolism; Sarcoplasmic Reticulum Calcium-Transporting ATPases - metabolism; Stroke Volume - physiology; Studies; Tetracycline - pharmacology; transgenic mouse; Troponin I - analysis; Ventricular Function, Left - physiology
• ISSN: 0735-1097; 1558-3597
• DOI: 10.1016/j.jacc.2010.11.052

Objectives This study tested the hypothesis that activation of adenylyl cyclase 6 (AC6) expression in cardiac myocytes improves calcium uptake and left ventricular (LV) function in aging mice. Background Aging hearts exhibit impaired β-adrenergic receptor signaling and LV dysfunction. Methods Twenty-month-old mice with cardiac-directed and regulated AC6 expression were randomized into 2 groups, and AC6 expression was activated in 1 group (AC6-On) but not the other (AC6-Off). One month later, LV function and sarcoplasmic reticulum calcium uptake were assessed. Results AC6 expression was associated with increased LV contractility, as reflected by ejection fraction (p = 0.02), rate of pressure development (p = 0.002), and slope of the LV end-systolic pressure-volume relationship (p = 0.04). No changes in LV weight to tibial length ratio, LV fibrosis, and expression of fetal genes (atrial natriuretic factor, α-skeletal muscle actin, and β-myosin heavy chain) and collagens were observed between AC6-On and AC6-Off groups. However, LV samples from AC6-On mice showed increases in: isoproterenol-stimulated cAMP production (p = 0.04), cAMP-dependent protein kinase activity (p < 0.0004), phosphorylation of phospholamban (at Ser16 site; p = 0.04) and cardiac troponin I (at Ser23/24 sites; p = 0.01), velocity of sarcoplasmic reticulum calcium uptake (p < 0.0001), and sarcoplasmic reticulum calcium-ATPase2a (SERCA2a) affinity for calcium (p < 0.0001). Finally, we found that AC6 expression increased sarcoplasmic reticulum calcium storage in cardiac myocytes isolated from 23-month-old rats. In contrast, AC6 expression in 7-month-old mice did not change LV function and calcium uptake. Conclusions These results indicate that activation of cardiac AC6 expression improves impaired function of aged hearts through improved calcium uptake.