Metallothionein prevents high-fat diet-induced cardiac contractile dysfunction -: Role of peroxisome proliferator-activated receptor γ coactivator 1α and mitochondrial biogenesis
Metallothionein prevents high-fat diet-induced cardiac contractile dysfunction -: Role of peroxisome proliferator-activated receptor γ coactivator 1α and mitochondrial biogenesis
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DOI：
10.2337/db06-1596
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发表时间：
2007-09-01
期刊：
影响因子：
7.7
通讯作者：
Ren, Jun
中科院分区：
文献类型：
--
作者：
Dong, Feng;Li, Qun;Ren, Jun
肥胖与氧化应激、线粒体和心肌功能障碍有关，尽管它们之间的相互作用仍然难以捉摸。本研究旨在评估自由基清除剂金属硫蛋白对高脂饮食诱导的心肌、细胞内Ca 2+和线粒体功能障碍的影响。FVB和金属硫蛋白转基因小鼠喂食高脂肪或低脂肪饮食5个月以诱导肥胖。超声心动图显示高脂喂养的FVB小鼠缩短分数降低，收缩末期直径增加和心脏肥大。高脂喂养FVB小鼠的心肌细胞显示活性氧（ROS）产生增强，收缩和细胞内Ca 2+缺陷，包括缩短峰值和缩短/再充盈最大速度降低，再充盈持续时间延长，细胞内Ca 2+升高和清除减少。透射显微镜观察到明显的线粒体损伤，线粒体密度降低。蛋白质印迹分析显示，在高脂饮食喂养的FVB小鼠的心脏中，核因子Foxo 3a的磷酸化增强，而Foxo 3a、Foxo 1a、pFoxo 1a、沉默信息调节因子（Sirt）、Akt和pAkt没有变化。过氧化物酶体增殖物激活受体γ辅激活因子-la（PGC-1 α）是线粒体生物合成的关键调节因子，其被高脂饮食喂养和体外棕榈酸处理显著抑制。RT-PCR进一步描述了降低的PGC-1 α水平。下游核呼吸因子1和2、线粒体转录因子A和线粒体DNA拷贝数。有趣的是，高脂饮食诱导的ROS、心肌收缩、线粒体和细胞信号传导的改变被金属硫蛋白所否定，除了pFoxo 3a。这些数据表明，金属硫蛋白可以防止高脂饮食诱导的心功能障碍，这可能与PGC-1 α的上调和线粒体生物合成的保护有关
Obesity is associated with oxidative stress and mitochondrial and myocardial dysfunction, although interaction among which remains elusive. This study was designed to evaluate the impact of the free radical scavenger metallothionein on high-fat diet-induced myocardial, intracellular Ca2+, and mitochondrial dysfunction. FVB and metallothionein transgenic mice were fed a high- or low-fat diet for 5 months to induce obesity. Echocardiography revealed decreased fractional shortening, increased end-systolic diameter, and cardiac hypertrophy in high-fat-fed FVB mice. Cardiomyocytes from high-fat-fed FVB mice displayed enhanced reactive oxygen species (ROS) production, contractile and intracellular Ca2+ defects including depressed peak shortening and maximal velocity of shortening/relengthening, prolonged duration of relengthening, and reduced intracellular Ca2+ rise and clearance. Transmission microscopy noted overt mitochondrial damage with reduced mitochondrial density. Western blot analysis revealed enhanced phosphorylation of nuclear factor Foxo3a without changes in Foxo3a, Foxo1a, pFoxo1a, silent information regulator (Sirt), and Akt and pAkt in hearts of high-fat diet-fed FVB mice. The peroxisome proliferator-activated receptor gamma coactivator-la (PGC-1 alpha), a key regulator of mitochondrial biogenesis, was significantly depressed by high-fat diet feeding and in vitro palmitic acid treatment. RT-PCR further depicted reduced levels of the PGC-1 alpha. downstream nuclear respiratory factors 1 and 2, mitochondrial transcription factor A, and mitochondrial DNA copy number in hearts of high-fat-fed FVB mice. Intriguingly, the high-fat diet-induced alterations in ROS, myocardial contractile, and mitochondrial and cell signaling were negated by metallothionein, with the exception of pFoxo3a. These data suggest that metallothionein may protect against high-fat diet-induced cardiac dysfunction possibly associated with upregulation of PGC-1 alpha and preservation of mitochondrial biogenesis