Preservation of myocardial β-adrenergic receptor signaling delays the development of heart failure after myocardial infarction

When the heart fails, there is often a constellation of biochemical alterations of the beta-adrenergic receptor (beta AR) signaling system, reading to the lass of cardiac inotropic reserve. beta AR down-regulation and functional uncoupling are mediated through enhanced activity of the beta AR kinase (beta ARK1), the expression of which is increased in ischemic and failing myocardium. These changes are widely viewed as representing an adaptive mechanism, which protects the heart against chronic activation. In this study, we demonstrate, using in vivo intracoronary adenoviral-mediated gene delivery of a peptide inhibitor of beta ARK1 (beta ARKct), that the desensitization and down-regulation of beta ARs seen in the failing heart may actually be maladaptive. In a rabbit model of heart failure induced by myocardial infarction, which recapitulates the biochemical beta AR abnormalities seen in human heart failure, delivery of the beta ARKct transgene at the time of myocardial infarction prevents the rise in beta ARK1 activity and expression and thereby maintains beta AR density and signaling at normal levels. Rather than leading to deleterious effects, cardiac function is improved, and the development of heart failure is delayed. These results appear to challenge the notion that dampening of beta AR signaling in the failing heart is protective, and they may lead to novel therapeutic strategies to treat heart disease via inhibition of beta ARK1 and preservation of myocardial beta AR function.