Mammalian Target of Rapamycin (mTOR) Inhibition with Rapamycin Improves Cardiac Function in Type 2 Diabetic Mice POTENTIAL ROLE OF ATTENUATED OXIDATIVE STRESS AND ALTERED CONTRACTILE PROTEIN EXPRESSION
Mammalian Target of Rapamycin (mTOR) Inhibition with Rapamycin Improves Cardiac Function in Type 2 Diabetic Mice POTENTIAL ROLE OF ATTENUATED OXIDATIVE STRESS AND ALTERED CONTRACTILE PROTEIN EXPRESSION
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DOI：
10.1074/jbc.m113.521062
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发表时间：
2014-02-14
影响因子：
4.8
通讯作者：
Kukreja, Rakesh C.
中科院分区：
文献类型：
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作者：
Das, Anindita;Durrant, David;Kukreja, Rakesh C.
背景：哺乳动物雷帕霉素靶蛋白（mTOR）信号通路升高与糖尿病并发症有关。结果如下：mTOR抑制剂雷帕霉素改善2型糖尿病小鼠的代谢状态和心脏功能，减弱氧化应激，并改变抗氧化和收缩蛋白的表达。结论：雷帕霉素对糖尿病小鼠的代谢和心脏有一定的保护作用。重要性：抑制mTOR可能是治疗糖尿病相关并发症的一种新策略，mTOR信号通路的增强与糖尿病的发病机制有关，糖尿病的发病率和死亡率增加主要是由于心血管并发症。由于雷帕霉素抑制mTOR可防止缺血/再灌注损伤，因此我们假设雷帕霉素可预防与2型糖尿病（T2 D）相关的心功能障碍。我们还研究了雷帕霉素诱导的T2 D小鼠心脏功能保护的可能机制和新的蛋白质靶点。将成年雄性瘦素受体无效、纯合db/db或野生型小鼠每天用媒介物（5%DMSO）或雷帕霉素（0.25mg/kg，腹膜内）处理28天。通过超声心动图监测心脏功能，并通过蛋白质组学分析确定蛋白质靶点。雷帕霉素治疗显著降低db/db小鼠的体重、心脏重量、血浆葡萄糖、甘油三酯和胰岛素水平。雷帕霉素治疗改善db/db小鼠的缩短分数。通过谷胱甘肽水平和脂质过氧化反应测量的氧化应激在雷帕霉素治疗的db/db心脏中显著降低。雷帕霉素阻断db/db心脏中mTOR和S6的增强磷酸化，但不阻断AKT。蛋白质组学（通过二维凝胶和质谱）和蛋白质印迹分析确定了雷帕霉素治疗db/db心脏后几种细胞骨架/收缩蛋白（肌球蛋白轻链MLY 2，肌球蛋白重链6，肌球蛋白结合蛋白C），葡萄糖代谢蛋白（丙酮酸脱氢酶E1，PYGB，Pgm 2）和抗氧化蛋白（过氧化物氧还蛋白5，铁蛋白重链1）的显著变化。这些结果表明，长期雷帕霉素治疗预防T2 D小鼠的心功能障碍，可能是通过减弱氧化应激和改变抗氧化剂和收缩以及葡萄糖代谢蛋白表达。
Background: Elevated mammalian target of rapamycin (mTOR) signaling contributes to diabetic complications. Results: mTOR inhibitor, rapamycin, improves metabolic status and cardiac function, attenuates oxidative stress, and alters antioxidant and contractile protein expression in type 2 diabetic mice. Conclusion: Rapamycin may provide metabolic and cardiac benefits in diabetic mice. Significance: mTOR inhibition may be an attractive novel therapeutic strategy for diabetes-related complications.Elevated mammalian target of rapamycin (mTOR) signaling contributes to the pathogenesis of diabetes, with increased morbidity and mortality, mainly because of cardiovascular complications. Because mTOR inhibition with rapamycin protects against ischemia/reperfusion injury, we hypothesized that rapamycin would prevent cardiac dysfunction associated with type 2 diabetes (T2D). We also investigated the possible mechanisms and novel protein targets involved in rapamycin-induced preservation of cardiac function in T2D mice. Adult male leptin receptor null, homozygous db/db, or wild type mice were treated daily for 28 days with vehicle (5% DMSO) or rapamycin (0.25 mg/kg, intraperitoneally). Cardiac function was monitored by echocardiography, and protein targets were identified by proteomics analysis. Rapamycin treatment significantly reduced body weight, heart weight, plasma glucose, triglyceride, and insulin levels in db/db mice. Fractional shortening was improved by rapamycin treatment in db/db mice. Oxidative stress as measured by glutathione levels and lipid peroxidation was significantly reduced in rapamycin-treated db/db hearts. Rapamycin blocked the enhanced phosphorylation of mTOR and S6, but not AKT in db/db hearts. Proteomic (by two-dimensional gel and mass spectrometry) and Western blot analyses identified significant changes in several cytoskeletal/contractile proteins (myosin light chain MLY2, myosin heavy chain 6, myosin-binding protein C), glucose metabolism proteins (pyruvate dehydrogenase E1, PYGB, Pgm2), and antioxidant proteins (peroxiredoxin 5, ferritin heavy chain 1) following rapamycin treatment in db/db heart. These results show that chronic rapamycin treatment prevents cardiac dysfunction in T2D mice, possibly through attenuation of oxidative stress and alteration of antioxidants and contractile as well as glucose metabolic protein expression.