The β-adrenergic receptor kinase in heart failure

Heart failure (HF) remains a significant and increasing cause of worldwide morbidity and mortality. HF is less a disease than a common clinical endpoint resulting from diverse, but often co-existing etiologies—including hypertension, coronary artery disease, and viral cardiomyopathy. Regardless of the pathologic trigger, HF can be characterized by a series of specific, molecular changes in the diseased myocardium. Noteworthy among these changes are alterations in the β-adrenergic receptor (βAR) signaling cascade. βARs belong to the larger family of G-protein-coupled receptors (GPCRs) and modulate cardiac function by controlling the inotropic and chronotropic response to catecholamines. βARs, in turn, are regulated by GPCR kinases (GRKs). GRKs phosphorylate βARs, blocking downstream-signaling cascades and ultimately desensitizing the receptor to further catecholamine stimuli. Recent advances in transgenic mouse and gene therapy techniques have led to therapeutic strategies by manipulating βAR signaling, specifically through the inhibition of the β-adrenergic receptor kinase (βARK1 or GRK2), the predominant myocardial GRK. The purpose of this manuscript, then, is to review (1) the changes that occur to βAR-signaling pathways in HF, (2) the evidence from transgenic murine studies examining the consequences of βARK1 manipulation in the failing heart, and (3) the effectiveness of in vivo applications of βARK1-targeted gene therapy at ameliorating HF.