Targeted Inhibition of β-Adrenergic Receptor Kinase-1–Associated Phosphoinositide-3 Kinase Activity Preserves β-Adrenergic Receptor Signaling and Prolongs Survival in Heart Failure Induced by Calsequestrin Overexpression

ObjectivesDesensitization and down-regulation of β-adrenergic receptors (βARs) are prominent features of heart failure largely mediated by increased levels of βAR kinase-1 (βARK1).Backgroundβ-adrenergic receptor kinase 1 interacts with phosphoinositide-3 kinase (PI3K), and upon agonist stimulation, the βARK1/PI3K complex is recruited to agonist-stimulated βARs. Here we tested the hypothesis that in vivo selective inhibition of βARK1-associated PI3K activity would preserve βAR signaling and, therefore, improve cardiac function and survival in experimental heart failure.MethodsWe used a murine model of heart failure induced by calsequestrin (CSQ) cardiac-specific overexpression; CSQ mice were crossed with mice overexpressing in the heart a catalytically inactive PI3Kγ (PI3Kγinact) to competitively displace endogenous PI3K from βARK1.ResultsCatalytically inactive PI3KγPI3K overexpression in CSQ mice inhibited βARK1-associated PI3K activity, normalized βAR levels, and preserved βAR responsiveness to isoproterenol (ISO). Restoration of βAR signaling via PI3Kγinactoverexpression resulted in marked improvement of cardiac function and a significant prolongation of survival. Importantly, the effects of PI3Kγinactoverexpression were restricted to βAR signaling, because cellular PI3K signaling was unaltered, as shown by the similar activation of multiple downstream signaling pathways in both CSQ and CSQ/PI3Kγinactmice.ConclusionsThese data in the CSQ model of cardiac dysfunction indicate that membrane-targeted PI3K activity plays a detrimental role in heart failure, and its inhibition represents a novel therapeutic approach to ameliorate cardiac dysfunction and improve survival