Faculdade de Medicina, Universidade Federal do Cariri, Barbalha, CE, Brazil.
Departamento de Bioquímica, Instituto de Química, Universidade de São Paulo, Brazil.
J Nutr Biochem. 2018 Dec;62:87-94. doi: 10.1016/j.jnutbio.2018.08.008. Epub 2018 Sep 5.
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 HO 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.
氧化应激与心肌肥厚和相关心力衰竭的发病机制有关。心肌组织会对压力或容量超负荷做出反应，导致壁增厚或腔室扩大。如果这种情况持续存在，将会导致心脏组织功能障碍和氧化应激。热量限制（CR）是改善健康和延缓衰老的有力干预措施。在这里，我们研究了通过避免活性氧（ROS）产生和维持抗氧化酶活性，CR 是否可以预防体内异丙肾上腺素诱导的心肌肥厚。此外，我们还研究了线粒体 ATP 敏感性钾通道（mitoKATP）在心肌肥厚中的作用。通过每日卡路里摄入量减少 40%来诱导 CR。在 CR 或自由进食（对照）喂养 3 周后，用异丙肾上腺素（30mg/kg/天）腹腔内处理瑞士小鼠 8 天以诱导肥大。异丙肾上腺素处理的小鼠心脏重量/胫骨长度比和心脏蛋白水平升高。CR 小鼠的这些肥大标志物明显减少。异丙肾上腺素处理的 CR 小鼠的心脏组织产生的 HO 更少，蛋白质巯基氧化程度更低。此外，CR 阻断了心肌肥厚过程中抗氧化酶（过氧化氢酶、超氧化物歧化酶和谷胱甘肽过氧化物酶）活性的抑制。在肥大的心脏中，mitoKATP 的打开在分离的线粒体中受到抑制，这对热量限制敏感。最后，mitoKATP 抑制显著阻断了 CR 的保护作用。总之，我们的结果表明，CR 在心肌肥厚过程中改善了细胞内氧化还原平衡，并通过涉及 mitoKATP 激活的机制防止了这一过程。
