Adenylyl Cyclase Type 5 Disruption Prolongs Longevity and Protects the Heart against Stress

Abstract

We tested the hypothesis that longevity and stress resistance are mediated by common mechanisms. We have recently identified a novel, genetically engineered animal model, i.e., mice with adenylyl cyclase (AC) type 5 “knocked out” (AC5 KO), which live 30% longer than wild type (WT) animals and do not exhibit the cardiomyopathy and osteoporosis of old age. Thoracic aortic banding reduced left ventricular (LV) ejection fraction (LVEF) in WT (from 70 ± 2.8 to 57 ± 3.9%, P < 0.05), but this was not observed in AC5 KO mice. Chronic (1–2 wks) isoproterenol (ISO) infusion induced more effective desensitization in AC5 KO and less apoptosis. Mice with cardiac overexpression of either β1-adrenergic receptors (β1-AR Tg) or β2-adrenergic receptors (β2-AR Tg) exhibit the opposite pattern, i.e. development of cardiomyopathy and enhanced premature mortality and less resistance to stress with either chronic pressure overload or chronic catecholamine stimulation. Mating the AC5 KO with β-AR Tg mice rescued their cardiomyopathy. Thus, AC5 is an important mechanism regulating lifespan and stress resistance and protects the heart against stress and from the cardiomyopathy induced by chronically enhanced β-AR signaling. Since the mechanisms of stress resistance appear to involve more effective desensitization, inhibition of AC5 could be a novel approach to the therapy of heart failure.