The role of AMP-activate protein kinase (AMPK) in the regulation of cardiac hypertrophy

Abstract

Backgrond: The polyphenol resveratrol has been attributed to some of the cardioprotective effects of red wine consumption, including the ability to inhibit hypertrophy via its antioxidant properties. A recent discovery in hepatocytes showed that resveratrol can activate AMP-activated protein kinase (AMPK), a key regulator of cellular energy homeostasis. However, it is currently unknown whether resveratrol can also activate cardiac AMPK and the functional consequence of this. As we have shown that activation of AMPK inhibits protein synthesis associated with cardiac hypertrophy, we hypothesized that an additional mechanism by which resveratrol inhibits hypertrophy is via AMPK activation. 
 Methods: To investigate this, neonatal rat cardiac myocytes were treated with vehicle (Veh) or 50 µM resveratrol (Resv) for 24 hours and 10 µM phenylephrine (PE) to induce hypertrophy. Contributors of the hypertrophic response, such as protein synthesis and specific intracellular signalling pathways, were measured using [3H]-phenylalanine incorporation and immunoblot analysis, respectively. 
 Results: Activation of AMPK was achieved with resveratrol even in the presence of phenylephrine, as shown by increased AMPK phosphorylation (Veh+PE = 0.69±0.06 vs Resv+PE = 1.57±0.29 arbitrary units, p < 0.01). Resveratrol also significantly decreased protein synthesis induced by phenylephrine (Veh+PE = 45702.5±5252.9 vs Resv+PE = 32929.0±4512.9 disintegrations per minute, p < 0.05). This was associated with reduced activities of regulators of protein synthesis, namely p70S6 kinase and eukaryotic elongation factor-2 (eEF2). Specifically, resveratrol countered the effects of phenylephrine by blunting the increase in p70S6 kinase phosphorylation while partially restoring eEF2 phosphorylation. Furthermore, resveratrol dramatically decreased nuclear factor of activated T-cells (NFAT) promoter activity, as shown by reduced luciferase activity driven by a NFAT-responsive promoter (Veh+PE = 171100±7881 vs Resv+PE = 27530±5975 luciferase activity, p < 0.001). 
 Conclusions: As the calcineurin-NFAT pathway is thought to be involved in pathological hypertrophy, this provides further evidence that AMPK activation has therapeutic potential, and shows another mechanism by which resveratrol can prevent hypertrophic growth.