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PRECLINICAL STUDY

Targeted Inhibition of ß-Adrenergic Receptor Kinase-1-Associated Phosphoinositide-3 Kinase Activity Preserves ß-Adrenergic Receptor Signaling and Prolongs Survival in Heart Failure Induced by Calsequestrin Overexpression

Cinzia Perrino, MD^_*, Sathyamangla V. Naga Prasad, PhD^_*, Mrinali Patel^_*, Matthew J. Wolf, MD, PhD^_* and Howard A. Rockman, MD^_*,,_*

^_* Department of Medicine, Duke University Medical Center, Durham, North Carolina
Department of Cell Biology and Molecular Genetics, Duke University Medical Center, Durham, North Carolina

Manuscript received December 13, 2004; revised manuscript received January 28, 2005, accepted February 14, 2005.

^_* Reprint requests and correspondence: Dr. Howard A. Rockman, Departments of Medicine, Cell Biology, and Molecular Genetics DUMC 3104, Room 226 CARL Building, Durham, North Carolina 27710. (Email: h.rockman{at}duke.edu).

OBJECTIVES: Desensitization and down-regulation of ß-adrenergic receptors (ßARs) are prominent features of heart failure largely mediated by increased levels of ßAR kinase-1 (ßARK1).

BACKGROUND: ß-adrenergic receptor kinase 1 interacts with phosphoinositide-3 kinase (PI3K), and upon agonist stimulation, the ßARK1/PI3K complex is recruited to agonist-stimulated ßARs. Here we tested the hypothesis that in vivo selective inhibition of ßARK1-associated PI3K activity would preserve ßAR signaling and, therefore, improve cardiac function and survival in experimental heart failure.

METHODS: We used a murine model of heart failure induced by calsequestrin (CSQ) cardiac-specific overexpression; CSQ mice were crossed with mice overexpressing in the heart a catalytically inactive PI3K (PI3K_inact) to competitively displace endogenous PI3K from ßARK1.

RESULTS: Catalytically inactive PI3KPI3K overexpression in CSQ mice inhibited ßARK1-associated PI3K activity, normalized ßAR levels, and preserved ßAR responsiveness to isoproterenol (ISO). Restoration of ßAR signaling via PI3K_inact overexpression resulted in marked improvement of cardiac function and a significant prolongation of survival. Importantly, the effects of PI3K_inact overexpression were restricted to ßAR signaling, because cellular PI3K signaling was unaltered, as shown by the similar activation of multiple downstream signaling pathways in both CSQ and CSQ/PI3K_inact mice.

CONCLUSIONS: These data in the CSQ model of cardiac dysfunction indicate that membrane-targeted PI3K activity plays a detrimental role in heart failure, and its inhibition represents a novel therapeutic approach to ameliorate cardiac dysfunction and improve survival.

Abbreviations and Acronyms   ßAR = ß-adrenergic receptor   ßARK1 = ßAR kinase-1   cAMP = cyclic adenosine monophosphate   CSQ = calsequestrin   GSK = glycogen synthase kinase 3ß   ISO = isoproterenol   MAPKs = mitogen-activated protein kinases   PKB = protein kinase B   PI3K = phosphoinositide-3 kinase   PI3Kinact = catalytically inactive PI3K   WT = wild type   %FS = percent fractional shortening

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