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(Circulation. 2005;111:2579-2587.)
© 2005 American Heart Association, Inc.

Heart Failure

Restoration of ß-Adrenergic Receptor Signaling and Contractile Function in Heart Failure by Disruption of the ßARK1/Phosphoinositide 3-Kinase Complex

Cinzia Perrino, MD^*; Sathyamangla V. Naga Prasad, PhD^*; Jacob N. Schroder, MD; Jonathan A. Hata, MD; Carmelo Milano, MD; Howard A. Rockman, MD

From the Department of Medicine, Cell Biology and Molecular Genetics (C.P., S.V.N.P., H.A.R.), and Department of Surgery (J.N.S., J.A.H., C.M.), Duke University Medical Center, Durham, NC.

Correspondence to Howard A. Rockman, MD, Department of Medicine, Cell Biology and Molecular Genetics, DUMC 3104, Room 226, CARL Building, Durham, NC 27710. E-mail rockm001{at}mc.duke.edu

Received September 22, 2004; revision received January 10, 2005; accepted January 13, 2005.

Background— Desensitization and downregulation of myocardial ß-adrenergic receptors (ßARs) are initiated by the increase in ßAR kinase 1 (ßARK1) levels. By interacting with ßARK1 through the phosphoinositide kinase (PIK) domain, phosphoinositide 3-kinase (PI3K) is targeted to agonist-stimulated ßARs, where it regulates endocytosis. We tested the hypothesis that inhibition of receptor-targeted PI3K activity would alter receptor trafficking and ameliorate ßAR signaling, ultimately improving contractility of failing cardiomyocytes.

Methods and Results— To competitively displace PI3K from ßARK1, we generated mice with cardiac-specific overexpression of the PIK domain. Seven-day isoproterenol administration in wild-type mice induced desensitization of ßARs and their redistribution from the plasma membrane to early and late endosomes. In contrast, transgenic PIK overexpression prevented the redistribution of ßARs away from the plasma membrane and preserved their responsiveness to agonist. We further tested whether PIK overexpression could normalize already established ßAR 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 ßARK1-associated PI3K activity and marked desensitization and redistribution of ßARs 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 ßARs away from the plasma membrane that can be counteracted through a strategy that targets the ßARK1/PI3K complex.

Key Words: catecholamines • gene therapy • heart failure • receptors, adrenergic, beta

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