When the heart fails, there is often a constellation of biochemical alterations of the ␤-adrenergic receptor (␤AR) signaling system, leading to the loss of cardiac inotropic reserve. ␤AR down-regulation and functional uncoupling are mediated through enhanced activity of the ␤AR kinase (␤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 ␤ARK1 (␤ARKct), that the desensitization and down-regulation of ␤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 ␤AR abnormalities seen in human heart failure, delivery of the ␤ARKct transgene at the time of myocardial infarction prevents the rise in ␤ARK1 activity and expression and thereby maintains ␤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 ␤AR signaling in the failing heart is protective, and they may lead to novel therapeutic strategies to treat heart disease via inhibition of ␤ARK1 and preservation of myocardial ␤AR function.

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Background-Desensitization and downregulation of myocardial ␤-adrenergic receptors (␤ARs) are initiated by the increase in ␤AR kinase 1 (␤ARK1) levels. By interacting with ␤ARK1 through the phosphoinositide kinase (PIK) domain, phosphoinositide 3-kinase (PI3K) is targeted to agonist-stimulated ␤ARs, where it regulates endocytosis. We tested the hypothesis that inhibition of receptor-targeted PI3K activity would alter receptor trafficking and ameliorate ␤AR signaling, ultimately improving contractility of failing cardiomyocytes. Methods and Results-To competitively displace PI3K from ␤ARK1, we generated mice with cardiac-specific overexpression of the PIK domain. Seven-day isoproterenol administration in wild-type mice induced desensitization of ␤ARs and their redistribution from the plasma membrane to early and late endosomes. In contrast, transgenic PIK overexpression prevented the redistribution of ␤ARs away from the plasma membrane and preserved their responsiveness to agonist. We further tested whether PIK overexpression could normalize already established ␤AR abnormalities and ameliorate contractile dysfunction in a large animal model of heart failure induced by rapid ventricular pacing in pigs. Failing porcine hearts showed increased ␤ARK1-associated PI3K activity and marked desensitization and redistribution of ␤ARs to endosomal compartments. Importantly, adenoviral gene transfer of the PIK domain in failing pig myocytes resulted in reduced receptor-localized PI3K activity and restored to nearly normal agonist-stimulated cardiomyocyte contractility. Conclusions-These data indicate that the heart failure state is associated with a maladaptive redistribution of ␤ARs away from the plasma membrane that can be counteracted through a strategy that targets the ␤ARK1/PI3K complex. Key Words: catecholamines Ⅲ gene therapy Ⅲ heart failure Ⅲ receptors, adrenergic, beta A bnormalities in the ␤-adrenergic receptor (␤AR) signaling system such as a reduction in the number of ligand-accessible ␤ARs (downregulation) and diminished response to catecholamine stimulation of remaining receptors (desensitization) are hallmarks of heart failure. 1,2 However, whether changes in ␤AR signaling represent an adaptive and protective process, as some postulate, 3 or whether ␤AR dysregulation actually promotes deterioration of cardiac function 4 is still controversial. 3 Results from our previous studies suggest that chronic ␤AR dysfunction in the failing heart is maladaptive and contributes to the deterioration in cardiac function. 4 Indeed, a consistent and prominent feature of ␤-blocker therapy in heart failure is the reversal of ␤AR dysfunction. 5,6 Considerable evidence supports the concept that the chronic increase in circulating catecholamine levels is largely responsible for the ␤AR abnormalities found in failing hearts. 4 Agonist-induced receptor dysfunction begins with ␤AR phosphorylation by ␤ARK1, followed by ␤-arrestin binding that sterically interdicts further G-protein coupling and initiates the process of receptor intern...