Genetic manipulation of myocardial β-adrenergic receptor activation and desensitization

Heart failure (HF) represents one of the leading causes of morbidity and mortality in developed nations today. Although this disease process represents a final common endpoint for several entities, including hypertension, coronary artery disease, and cardiomyopathy, a predominant characteristic of end-stage HF is an altered β-adrenergic receptor signaling cascade. In the heart, β-adrenergic receptors (βARs), members of the superfamily of G-protein-coupled receptors (GPCRs), modulate cardiac function by controlling chronotropic, inotropic, and lusitropic responses to catecholamines of the sympathetic nervous system. In HF, βARs are desensitized and downregulated in a maladaptive response to chronic stimulation. This process is largely mediated by G-protein-coupled receptor kinases (GRKs), which phosphorylate GPCRs leading to functional uncoupling. The most abundant cardiac GRK, known as GRK2 or βAR kinase 1 (βARK1), is increased in human HF, and has been implicated in the pathogenesis of dysfunctional cardiac βAR signaling. The association of βARs and GRKs with impaired cardiac function has been extensively studied using transgenic mouse models, which have demonstrated that βARK1 plays a vital role in the regulation of myocardial βAR signaling. These findings have caused βARs and GRKs to be regarded as potential therapeutic targets, and gene therapy strategies have been used to manipulate the βAR signaling pathway in myocardium, leading to improved function in the compromised heart. Ultimately, these genetic modifications of the heart may represent new potential therapies for human HF.