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

Abstract

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.Pathological left ventricular hypertrophy is associated with coronary heart disease and all-cause mortality (1) and is a major clinical concern in cardiovascular medicine. At the cellular level, enlargement of the cardiac myocyte involves multiple events, including gene transcription and protein translation/ synthesis, which are regulated by protein kinase signaling cascades. For gene transcription, the calcineurin-nuclear factor of activated T cells (NFAT) 6 signaling pathway has been shown to play a major role in the development of pathological cardiac hypertrophy (2). Upon dephosphorylation by calcineurin, NFAT translocates to the nucleus of the cardiac myocyte where it mediates the transcription of numerous targets involved in hypertrophic growth (see Ref. 3 for review). In conjunction with alterations in gene expression, an important cellular process that must also occur during hypertrophy is enhanced protein synthesis. While the list of proteins involved in regulating protein synthesis in the cardiac myocyte is extensive, the p70S6 kinase (p70S6K) and eukaryotic elongation factor-2 (eEF2) play key roles in this process (4 -8). Although the p70S6K, eEF2, and NFAT pathways are distinct in many ways, their regulation, in some instances, appears to intersect as all three of these proteins can be regulated by two upstream kinases, AMP-activated protein kinase (AMPK) and Akt.Activation of Akt has been shown to promote cardiac hypertrophy via a number of pathways including the indirect activation of p70S6K (6) and the inhibition of glycogen synthase kinase-3␤ (GSK-3␤) (9). Whereas the pro-hypertrophic effects of Akt activation in the heart are well-established (10 -12), much less is known about the role of AMPK in the hypertrophic...

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