Background— Desensitization and downregulation of myocardial β-adrenergic receptors (βARs) are initiated by the increase in βAR kinase 1 (βARK1) levels. By interacting with βARK1 through the phosphoinositide kinase (PIK) domain, phosphoinositide 3-kinase (PI3K) is targeted to agonist-stimulated βARs, where it regulates endocytosis. We tested the hypothesis that inhibition of receptor-targeted PI3K activity would alter receptor trafficking and ameliorate βAR signaling, ultimately improving contractility of failing cardiomyocytes.

Methods and Results— To competitively displace PI3K from βARK1, we generated mice with cardiac-specific overexpression of the PIK domain. Seven-day isoproterenol administration in wild-type mice induced desensitization of βARs and their redistribution from the plasma membrane to early and late endosomes. In contrast, transgenic PIK overexpression prevented the redistribution of βARs away from the plasma membrane and preserved their responsiveness to agonist. We further tested whether PIK overexpression could normalize already established βAR 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 βARK1-associated PI3K activity and marked desensitization and redistribution of βARs 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 βARs away from the plasma membrane that can be counteracted through a strategy that targets the βARK1/PI3K complex.