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

Human heart failure is a complex clinical syndrome characterized by extensive abnormalities in the beta-adrenergic receptor (betaAR) system. Normalization of betaAR signalling consistently ameliorates cardiac dysfunction and survival in heart failure, suggesting that betaAR dysfunction may be intrinsically linked to the deterioration of cardiac performance. Agonist-dependent phosphorylation of betaARs by betaAR kinase 1 (betaARK1) initiates the processes of desensitization and downregulation, hallmarks of heart failure. Our recent studies have shown that betaARK1 forms a cytosolic complex with phosphoinositide 3-kinase (PI3K) and that translocation of betaARK1 to the plasma membrane also promotes the betaAR-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 betaAR-targeting of PI3Ks is consistently associated with abnormalities of betaAR signalling under pathological conditions, including pressure-overload hypertrophy and heart failure from different causes. In this review we will discuss the role of betaAR-targeted PI3K activity and novel experimental strategies to disrupt the betaARK1/PI3K complex and in turn ameliorate betaAR dysfunction and the progression of heart failure.