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

OBJECTIVES Desensitization and down-regulation of -adrenergic receptors ( ARs) are prominent features of heart failure largely mediated by increased levels of AR kinase-1 ( ARK1). BACKGROUND -adrenergic receptor kinase 1 interacts with phosphoinositide-3 kinase (PI3K), and upon agonist stimulation, the ARK1/PI3K complex is recruited to agonist-stimulated ARs. Here we tested the hypothesis that in vivo selective inhibition of ARK1-associated PI3K activity would preserve AR signaling and, therefore, improve cardiac function and survival in experimental heart failure. METHODS We 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 PI3K (PI3K inact) to competitively displace endogenous PI3K from ARK1. RESULTS Catalytically inactive PI3K PI3K overexpression in CSQ mice inhibited ARK1-associated PI3K activity, normalized AR levels, and preserved AR responsiveness to isoproterenol (ISO). Restoration of AR signaling via PI3K inact overexpression resulted in marked improvement of cardiac function and a significant prolongation of survival. Importantly, the effects of PI3K inact overexpression were restricted to AR signaling, because cellular PI3K signaling was unaltered, as shown by the similar activation of multiple downstream signaling pathways in both CSQ and CSQ/PI3K inact mice. CONCLUSIONS These 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. (J Am Coll ublished by Elsevier Inc. doi:10.1016/j.jacc.2005.02.062