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(Circulation Research. 2009;104:660.)
© 2009 American Heart Association, Inc.

Cellular Biology

p66Shc Links ₁-Adrenergic Receptors to a Reactive Oxygen Species-Dependent AKT-FOXO3A Phosphorylation Pathway in Cardiomyocytes

Jianfen Guo, Zoya Gertsberg, Nazira Ozgen, Susan F. Steinberg

From the Department of Pharmacology, Columbia University, New York.

Correspondence to Susan F. Steinberg, MD, Department of Pharmacology, College of Physicians and Surgeons, Columbia University, 630 West 168 St, New York, NY 10032. E-mail sfs1{at}columbia.edu

p66Shc is an adapter protein that is induced by hypertrophic stimuli and has been implicated as a major regulator of reactive oxygen species (ROS) production and cardiovascular oxidative stress responses. This study implicates p66Shc in an ₁-adrenergtic receptor (₁-AR) pathway that requires the cooperative effects of protein kinase (PK)C and PKC and leads to AKT-FOXO3a phosphorylation in cardiomyocytes. ₁-ARs promote p66Shc-YY^239/240 phosphorylation via a ROS-dependent mechanism that is localized to caveolae and requires epidermal growth factor receptor (EGFR) and PKC activity. ₁-ARs also increase p66Shc-S³⁶ phosphorylation via an EGFR transactivation pathway involving PKC. p66Shc links ₁-ARs to an AKT signaling pathway that selectively phosphorylates/inactivates FOXO transcription factors and downregulates the ROS-scavenging protein manganese superoxide dismutase (MnSOD); the ₁-AR-p66Shc-dependent pathway involving AKT does not regulate GSK3. Additional studies show that RNA interference-mediated downregulation of endogenous p66Shc leads to the derepression of FOXO3a-regulated genes such as MnSOD, p27Kip1, and BIM-1. p66Shc downregulation also increases proliferating cell nuclear antigen expression and induces cardiomyocyte hypertrophy, suggesting that p66Shc exerts an antihypertrophic action in neonatal cardiomyocytes. The novel ₁-AR- and ROS-dependent pathway involving p66Shc identified in this study is likely to contribute to cardiomyocyte remodeling and the evolution of heart failure.

Key Words: p66Shc • ₁-adrenergic receptors • protein kinase C • ROS • AKT

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