2009 Thomas W. Smith Memorial Lecture—GRK2 Inhibition as a Novel Therapeutic Target in Heart Failure

For more than 15 years, our laboratory has been researching the role of the G protein–coupled receptor kinases (GRKs) in myocardial function. This includes how GRKs are involved in the cardiovascular pathological processes of hypertension, ventricular hypertrophy, and heart failure. Studies with GRK2 (also known as β ARK1) have shown, from cell studies to whole-animal studies, that the increased activity of this kinase is pathological to the cardiomyocyte. Importantly, lowering its expression or activity has led to beneficial effects in several animal models of heart failure. Most recently, studies in myocyte-specific GRK2-knockout mice have revealed that the loss of GRK2 in heart cells prevents the development of heart failure after a myocardial infarction. In separate animal studies, gene therapy with a GRK2 inhibitor peptide has shown that lowering the activity of this kinase can reverse ventricular contractile failure and also adverse remodeling. Large animal preclinical studies are being done with gene therapy; however, development of small-molecule inhibitors of GRK2 is warranted. This lecture will focus on the translational continuum of research for the past 15+ years in the development of GRK2 as a definitive target for heart failure therapy. The lecture will also include new data supporting unique roles for GRK2 in myocardial signaling and function.