Calorie restriction attenuates hypertrophy-induced redox imbalance and mitochondrial ATP-sensitive K+ channel repression.

Oxidative stress has been implicated in the pathogenesis of cardiac hypertrophy and associated heart failure. Cardiac tissue grows in response to pressure or volume overload, leading to wall thickening or chamber enlargement. If sustained, this condition will lead to a dysfunctional cardiac tissue and oxidative stress. Calorie restriction (CR) is a powerful intervention to improve health and delay aging. Here, we investigated whether calorie restriction in mice prevented isoproterenol-induced cardiac hypertrophy in vivo by avoiding reactive oxygen species (ROS) production and maintaining antioxidant enzymatic activity. Additionally, we investigated the involvement of mitochondrial ATP-sensitive K+ channels (mitoKATP) in cardiac hypertrophy. CR was induced by 40% reduction in daily calorie ingestion. After 3 weeks on CR or ad libitum (Control) feeding, Swiss mice were treated intraperitoneally with isoproterenol (30 mg/kg per day) for 8 days to induce hypertrophy. Isoproterenol-treated mice had elevated heart weight/tibia length ratios and cardiac protein levels. These gross hypertrophic markers were significantly reduced in CR mice. Cardiac tissue from isoproterenol-treated CR mice also produced less H2O2 and had lower protein sulfydryl oxidation. Additionally, calorie restriction blocked hypertrophic-induced antioxidant enzyme (catalase, superoxide dismutase and glutathione peroxidase) activity repression during cardiac hypertrophy. MitoKATP opening was repressed in isolated mitochondria from hypertrophic hearts, in a manner sensitive to calorie restriction. Finally, mitoKATP inhibition significantly blocked the protective effects of calorie restriction. Altogether, our results suggest that CR improves intracellular redox balance during cardiac hypertrophy and prevents this process in a mechanism involving mitoKATP activation.