Novel distribution of calreticulin to cardiomyocyte mitochondria and its increase in a rat model of dilated cardiomyopathy
Novel distribution of calreticulin to cardiomyocyte mitochondria and its increase in a rat model of dilated cardiomyopathy
复制标题
扩张型心肌病大鼠模型中钙网蛋白在心肌细胞线粒体中的新分布及其增加
DOI：
10.1016/j.bbrc.2014.04.156
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发表时间：
2014-06-20
影响因子：
3.1
通讯作者：
Xue, Jiahong
中科院分区：
文献类型：
--
作者：
Zhang, Ming;Wei, Jin;Xue, Jiahong
背景资料：钙网蛋白（CRT），内质网的钙结合伴侣，也可以发现在几个其他位置，包括细胞质，细胞核，分泌颗粒，质膜外侧，和细胞外基质。CRT是否定位于心肌细胞的线粒体，以及这种定位是否受到影响下DCM.Methods和结果：DCM模型在大鼠中产生的每日口服呋喃唑酮30周。超声心动图和血流动力学研究表明扩张型心肌病大鼠左心室尺寸增大，收缩和舒张功能降低。免疫电镜和Westernblot显示心肌细胞线粒体内有CRT存在，且DCM心肌细胞线粒体CRT含量增加（P < 0.05）。形态计量学分析显示DCM心脏中显著的心肌细胞凋亡和线粒体肿胀，嵴断裂或溶解。与对照组相比，模型组大鼠心肌线粒体膜电位水平、细胞色素c氧化酶和琥珀酸脱氢酶活性明显降低（P < 0.05），心肌细胞凋亡指数、caspase-9和caspase-3活性明显升高（P < 0.05）。Pearson直线相关分析显示，CRT线粒体含量与线粒体功能呈负相关，与心肌细胞凋亡指数呈正相关（P < 0.001）。与对照组相比，模型组心肌细胞线粒体细胞色素c蛋白表达水平和STAT 3磷酸化活性均显著降低（P < 0.05）。结论：DCM心肌CRT定位于心肌细胞线粒体，线粒体含量增加。(C)2014爱思唯尔公司All rights reserved.
Background: Calreticulin (CRT), a Ca2+-binding chaperone of the endoplasmic reticulum, can also be found in several other locations including the cytosol, nucleus, secretory granules, the outer side of the plasma membrane, and the extracellular matrix. Whether CRT is localized at mitochondria of cardiomyocytes and whether such localization is affected under DCM are still unclear.Methods and results: The DCM model was generated in rats by the daily oral administration of furazolidone for thirty weeks. Echocardiographic and hemodynamic studies demonstrated enlarged left ventricular dimensions and reduced systolic and diastolic function in DCM rats. Immuno-electron microscopy and Western blot showed that CRT was present in cardiomyocyte mitochondria and the mitochondrial content of CRT was increased in DCM hearts (P < 0.05). Morphometric analysis showed notable myocardial apoptosis and mitochondrial swelling with fractured or dissolved cristae in the DCM hearts. Compared with the control group, the mitochondrial membrane potential level of the freshly isolated cardiac mitochondria and the enzyme activities of cytochrome c oxidase and succinate dehydrogenase in the model group were significantly decreased (P < 0.05), and the myocardial apoptosis index and the caspase activities of caspase-9 and caspase-3 were significantly increased (P < 0.05). Pearson linear correlation analysis showed that the mitochondrial content of CRT had negative correlations with the mitochondrial function, and a positive correlation with myocardial apoptosis index (P < 0.001). The protein expression level of cytochrome c and the phosphorylation activity of STAT3 in the mitochondrial fraction were significantly decreased in the model group compared with the control group (P < 0.05).Conclusions: These data demonstrate that CRT is localized at cardiomyocyte mitochondria and its mitochondrial content is increased in DCM hearts. (C) 2014 Elsevier Inc. All rights reserved.