Reciprocal in vivo regulation of myocardial g protein-coupled receptor kinase expression by β-adrenergic receptor stimulation and blockade

Background-Impaired myocardial beta-adrenergic receptor (beta AR) signaling, including desensitization and functional uncoupling, is a characteristic of congestive heart failure. A contributing mechanism for this impairment may involve enhanced myocardial beta-adrenergic receptor kinase (beta ARK1) activity because levels of this beta AR-desensitizing G protein-coupled receptor kinase (GRK) are increased in heart failure. An hypothesis has emerged that increased sympathetic nervous system activity associated with heart failure might be the initial stimulus for beta AR signaling alterations, including desensitization. We have chronically treated mice with drugs that either activate or antagonize beta ARs to study the dynamic relationship between beta AR activation and myocardial levels of beta ARK1. Methods and Results-Long-term in vivo stimulation of beta ARs results in the impairment of cardiac beta AR signaling and increases the level of expression (mRNA and protein) and activity of beta ARK1 but not that of GRK5, a second GRK abundantly expressed in the myocardium. Long-term beta-blocker treatment, including the use of carvedilol, improves myocardial beta AR signaling and reduces beta ARK1 levels in a specific and dose-dependent manner. Identical results were obtained in vitro in cultured cells, demonstrating that the regulation of GRK expression is directly linked to beta AR signaling. Conclusions-This report demonstrates, for the first time, that beta AR stimulation can significantly increase the expression of beta ARK1, whereas beta-blockade decreases expression. This reciprocal regulation of beta ARK1 documents a novel mechanism of ligand-induced beta AR regulation and provides important insights into the potential mechanisms responsible for the effectiveness of beta-blockers, such as carvedilol, in the treatment of heart failure.