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J. Biol. Chem., Vol. 283, Issue 35, 24194-24201, August 29, 2008

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Resveratrol Inhibits Cardiac Hypertrophy via AMP-activated Protein Kinase and Akt^*

Anita Y. M. Chan^¶1, Vernon W. Dolinsky², Carrie-Lynn M. Soltys, Benoit Viollet^||**3, Shairaz Baksh, Peter E. Light^¶4, and Jason R. B. Dyck^¶5

From the Cardiovascular Research Group and the Departments of Pediatrics and ^¶Pharmacology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Alberta T6G 2S2, Canada, the ^||Institut Cochin, Université Paris Descartes, CNRS (UMR 8104), 75014 Paris, France, and ^**INSERM U567, 75014 Paris, France

Whereas studies involving animal models of cardiovascular disease demonstrated that resveratrol is able to inhibit hypertrophic growth, the mechanisms involved have not been elucidated. Because studies in cells other than cardiomyocytes revealed that AMP-activated protein kinase (AMPK) and Akt are affected by resveratrol, we hypothesized that resveratrol prevents cardiac myocyte hypertrophy via these two kinase systems. Herein, we demonstrate that resveratrol reduces phenylephrine-induced protein synthesis and cell growth in rat cardiac myocytes via alterations of intracellular pathways involved in controlling protein synthesis (p70S6 kinase and eukaryotic elongation factor-2). Additionally, we demonstrate that resveratrol negatively regulates the calcineurin-nuclear factor of activated T cells pathway thus modifying a critical component of the transcriptional mechanism involved in pathological cardiac hypertrophy. Our data also indicate that these effects of resveratrol are mediated via AMPK activation and Akt inhibition, and in the case of AMPK, is dependent on the presence of the AMPK kinase, LKB1. Taken together, our data suggest that resveratrol exerts anti-hypertrophic effects by activating AMPK via LKB1 and inhibiting Akt, thus suppressing protein synthesis and gene transcription.

Received for publication, April 15, 2008 Accepted for publication May 28, 2008.

^* This research was supported in part by grants from the Canadian Institutes of Health Research (CIHR) and the Heart and Stroke Foundation of Canada (HSFC). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Recipient of an HSFC Doctoral Research Award and an Alberta Heritage Foundation for Medical Research (AHFMR) MD/PhD Studentship Award and is a CIHR Strategic Training Fellow in TORCH (Tomorrow's Research Cardiovascular Health Professionals).

² Supported by AHFMR and HSFC Postdoctoral Fellowships.

³ Supported by an integrated project from the European Commission (LSHM-CT-2004-005272/exgenesis) and Agence Nationale de la Recherche (ANR Physiopathologie des Maladies Humaines).

⁴ AHFMR Senior Scholar.

⁵ AHFMR Senior Scholar and holds a Canada Research Chair in Molecular Biology of Heart Disease and Metabolism. To whom correspondence should be addressed: 430 Heritage Medical Research Centre, University of Alberta, Edmonton, Alberta T6G 2S2, Canada. Tel.: 1-780-492-0314; Fax: 1-780-492-9753; E-mail: jason.dyck{at}ualberta.ca.

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