Published Online
on May 16, 2005

A more recent version of this article appeared on May 24, 2005

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Submitted on September 22, 2004
Revised on January 10, 2005
Accepted on January 13, 2005

Restoration of -Adrenergic Receptor Signaling and Contractile Function in Heart Failure by Disruption of the ARK1/Phosphoinositide 3-Kinase Complex

Cinzia Perrino MD, Sathyamangla V. Naga Prasad PhD, Jacob N. Schroder MD, Jonathan A. Hata MD, Carmelo Milano MD, and 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.

^* To whom correspondence should be addressed. E-mail: rockm001{at}mc.duke.edu.

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 • gene therapy • heart failure • receptors, adrenergic, beta

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