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

Human heart failure is a complex clinical syndrome characterized by extensive abnormalities in the beta-adrenergic receptor (beta AR) system. Normalization of beta AR signalling consistently ameliorates cardiac dysfunction and survival in heart failure, suggesting that beta AR dysfunction may be intrinsically linked to the deterioration of cardiac performance. Agonist-dependent phosphorylation of beta ARs by beta AR kinase 1 (beta ARK1) initiates the processes of desensitization and downregulation, hallmarks of heart failure. Our recent studies have shown that beta ARK1 forms a cytosolic complex with phosphoinositide 3-kinase (PI3K) and that translocation of beta ARK1 to the plasma membrane also promotes the beta AR-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 beta AR-targeting of PI3Ks is consistently associated with abnormalities of beta AR signalling under pathological conditions, including pressure-overload hypertrophy and heart failure from different causes. In this review we will discuss the role of beta AR-targeted PI3K activity and novel experimental strategies to disrupt the beta ARK1/PI3K complex and in turn ameliorate beta AR dysfunction and the progression of heart failure. (c) 2006 Elsevier Inc. All rights reserved.