Genetic manipulation of myocardial beta-adrenergic receptor activation and desensitization

Abstract

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 beta-adrenergic receptor signaling cascade. In the heart, beta-adrenergic receptors (beta ARs), 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, beta ARs 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 beta AR kinase 1 (beta ARK1), is increased in human HF, and has been implicated in the pathogenesis of dysfunctional cardiac beta AR signaling. The association of beta ARs and GRKs with impaired cardiac function has been extensively studied using transgenic mouse models, which have demonstrated that beta ARK1 plays a vital role in the regulation of myocardial beta AR signaling. These findings have caused beta ARs and GRKs to be regarded as potential therapeutic targets, and gene therapy strategies have been used to manipulate the beta AR 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.