GRK2 inhibition in heart failure: something old, something new.

Despite significant advances in pharmacological and clinical treatment, heart failure (HF) remains the number one killer disease in the western world. HF is a chronic and progressive clinical syndrome mainly characterized by reduction in left ventricular ejection fraction and adverse remodeling of the myocardium. One of its hallmark molecular abnormalities is elevation of cardiac G protein-coupled receptor (GPCR) kinase (GRK)-2, originally termed beta-adrenergic receptor kinase-1 (βARK1), a member of the GRK family of serine/threonine protein kinases which phosphorylate and desensitize GPCRs. Up-regulated GRK2 in the heart underlies the diminished contractile responsiveness of the heart to positive inotropes, as it abrogates the pro-contractile signaling of various important cardiac receptors: mainly β-adrenergic receptors (βARs), but also angiotensin II type 1 receptors (AT(1)Rs), etc. Thus, cardiac-specific GRK2 inhibition via various transgenic approaches is postulated to combat chronic HF symptoms by increasing cardiac function, and even be salutary in some cases by increasing survival. This has been extensively documented over the past 15 years through a vast series of preclinical studies on animals of all sizes and shapes, from small mice up to large rabbits and pigs closely resembling human physiology, and genetically manipulated to have cardiac GRK2 inhibited or deleted, transiently or permanently. However, over the past several years, it has become increasingly clear that GRK2, like other members of the GRK family, exerts additional effects that can aggravate HF, in addition to merely blunt cardiac contractility by opposing cardiac βAR G protein-mediated signaling. One of these newly discovered cardiotoxic effects of GRK2, uncovered by our laboratory, is promotion by adrenal GRK2 of sympathetic hyperactivity of the failing heart, a significant morbidity factor in HF, targeted therapeutically nowadays by the use of beta-blockers in HF pharmacotherapy. Thus, new avenues for therapeutic exploitation of GRK2 inhibition in HF treatment might be possible in the near future. The present review gives first a brief account of what has already been documented about the benefits of cardiac GRK2 genetic manipulation in HF as a positive inotropic therapy for the disease, and then goes on to discuss in detail the intriguing new possibility that has emerged of lowering GRK2 activity in the adrenal gland, which could constitute a novel sympatholytic therapy for HF that helps relieve the devastatingly cardiotoxic sympathetic overload of the failing heart.