Desensitization and down-regulation of β-adrenergic receptors (βARs) are prominent features of heart failure largely mediated by increased levels of βAR kinase-1 (βARK1).

β-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.

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 PI3Kγ (PI3Kγ_inact) to competitively displace endogenous PI3K from βARK1.

Catalytically 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 PI3Kγ_inactoverexpression resulted in marked improvement of cardiac function and a significant prolongation of survival. Importantly, the effects of PI3Kγ_inactoverexpression 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/PI3Kγ_inactmice.

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.