The beta-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 beta-adrenergic receptor (betaAR) signaling cascade. betaARs belong to the larger family of G-protein-coupled receptors (GPCRs) and modulate cardiac function by controlling the inotropic and chronotropic response to catecholamines. betaARs, in turn, are regulated by GPCR kinases (GRKs). GRKs phosphorylate betaARs, 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 betaAR signaling, specifically through the inhibition of the beta-adrenergic receptor kinase (betaARK1 or GRK2), the predominant myocardial GRK. The purpose of this manuscript, then, is to review (1). the changes that occur to betaAR-signaling pathways in HF, (2). the evidence from transgenic murine studies examining the consequences of betaARK1 manipulation in the failing heart, and (3). the effectiveness of in vivo applications of betaARK1-targeted gene therapy at ameliorating HF.
D000818:Animals; D017868:Cyclic AMP-Dependent Protein Kinases / Q000502:physiology*; D015316:Genetic Therapy; D006333:Heart Failure; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D008954:Models, Biological; D008957:Models, Genetic; D009206:Myocardium / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism; D015398:Signal Transduction; D051552:beta-Adrenergic Receptor Kinases
D043562:Receptors, G-Protein-Coupled; D017868:Cyclic AMP-Dependent Protein Kinases; D051552:beta-Adrenergic Receptor Kinases