GRK2 as a novel gene therapy target in heart failure

Abstract 

Despite significant advances in pharmacological and clinical treatment, heart failure (HF) remains a leading cause of morbidity and mortality worldwide. HF is a chronic and progressive clinical syndrome characterized by a reduction in left ventricular (LV) ejection fraction and adverse remodeling of the myocardium. The past several years have seen remarkable progress using animal models in unraveling the cellular and molecular mechanisms underlying HF pathogenesis and progression. These studies have revealed potentially novel therapeutic targets/strategies. The application of cardiac gene transfer, which allows for the manipulation of targets in cardiomyocytes, appears to be a promising therapeutic tool in HF. β-adrenergic receptor (βAR) dysfunction represents a hallmark abnormality of chronic HF, and increased G protein-coupled receptor kinase 2 (GRK2) levels/activity in failing myocardium is among these alterations. In the past 15years, several animal studies have shown that expression of a peptide inhibitor of GRK2 (βARKct) can improve the contractile function of failing myocardium including promoting reverse remodeling of the LV. Therefore, data support the use of the βARKct as a promising candidate for therapeutic application in human HF. Importantly, recent studies in cardiac-specific GRK2 knockout mice have corroborated GRK2 being pathological in failing myocytes. The purpose of this review is to discuss: 1) the alterations of βAR signaling that occur in HF, 2) the evidence from transgenic mouse studies investigating the impact of GRK2 manipulation in failing myocardium, 3) the therapeutic efficacy of in vivo βARKct gene therapy in HF, and 4) the intriguing possibility of lowering HF-related sympathetic nervous system hyperactivity by inhibiting GRK2 activity in the adrenal gland. This article is part of a Special Section entitled “Special Section: Cardiovascular Gene Therapy”.

Research Highlights 

Keywords: β-adrenergic receptor, Heart failure, Gene therapy, G protein-coupled receptor kinase, βARKct, Neurohormonal feedback