Published online before print January 22, 2009, doi: 10.1161/CIRCRESAHA.108.186288
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Submitted on August 26, 2008
Revised on January 7, 2009
Accepted on January 12, 2009
p66Shc Links 
1-Adrenergic Receptors to a Reactive Oxygen Species–Dependent AKT-FOXO3A Phosphorylation Pathway in Cardiomyocytes
Jianfen Guo ;
From the Department of Pharmacology, Columbia University, New York.
* To whom correspondence should be addressed. 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-YY239/240 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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