Targeted inhibition of phosphoinositide 3-kinase activity as a novel strategy to normalize β-adrenergic receptor function in heart failure

Abstract

Human heart failure is a complex clinical syndrome characterized by extensive abnormalities in the β-adrenergic receptor (βAR) system. Normalization of βAR signalling consistently ameliorates cardiac dysfunction and survival in heart failure, suggesting that βAR dysfunction may be intrinsically linked to the deterioration of cardiac performance. Agonist-dependent phosphorylation of βARs by βAR kinase 1 (βARK1) initiates the processes of desensitization and downregulation, hallmarks of heart failure. Our recent studies have shown that βARK1 forms a cytosolic complex with phosphoinositide 3-kinase (PI3K) and that translocation of βARK1 to the plasma membrane also promotes the βAR-targeting of PI3Ks. At the plasma membrane, the generation of 3′-phosphorylated phosphatidylinositols by PI3K is required in the process of endocytosis, a prodrome to receptor downregulation. A large body of data now indicates that βAR-targeting of PI3Ks is consistently associated with abnormalities of βAR signalling under pathological conditions, including pressure-overload hypertrophy and heart failure from different causes. In this review we will discuss the role of βAR-targeted PI3K activity and novel experimental strategies to disrupt the βARK1/PI3K complex and in turn ameliorate βAR dysfunction and the progression of heart failure.