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Research in the mechanism of ischemic cell death of cardiomyocyte and the role of mitochondria

心肌细胞缺血性细胞死亡机制及线粒体作用的研究

基本信息

批准号：
13670716
负责人：
IKEDA Yasuhiro
金额：
$ 2.3万
依托单位：
Yamaguchi University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2001
资助国家：
日本
起止时间：
2001 至 2002
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-13670716/
关键词：
Ischemia reperfusion injury mitochondria intracellular calcium superoxide potassium channel preconditioning protein kinase C Ischemic preconditioning ミトコンドリアK-ATPchannel ベータ遮断薬 Ca paradox 低体温アポトーシス ischemic preconditioning 心

项目摘要

In the rat ischemia-reperfusion model, the effect of ischemic preconditioning, mitochondrial K-ATP channel openers, nicorandil and diazoxide, on the reduction of infarct size was tested. All these interventions reduced the infarct size significantly, indicating the importance of the opening of mitochondrial K-ATP cahnnels for the reduction of ischemic injury. The left ventricular remodeling was assessed by the LV pressure-volume relation at 3 weeks after infarction. The LV remodeling was attenuated by the opening of mitochondrial K-ATP channels and the extent of remodeling and infarct size was correlated. The mechanism of opening the mitochondrial K-ATP channels is distinct between nicorandil and diazoxide, since the effect of nicorandil was partially inhibited by PKC inhibitor, although the effect of diazoxide was not influenced. The PKC isoform translocation from cytosolic to mitochondrial fraction was assessed by Western blotting. This revealed that the PKC ε and δ was translocated to mitochondrial fraction by nicorandil, which is inhibited by PKC inhibitor. Furthermore, NO quencher reduced the translocation of these isoforms to the mitochondrial fraction indicates that the NO donor effect of nicorandil activates the PKC ε and δ, which subsequently activates the mitochondrial K-ATP cahnnels synergistically with the direct opening effect of nicorandil. The adaptor protein in mitochondria which bind to PKC ε and δ were explored by immunoprecipitation and new adaptor proteins are detected, which may play an important role for the activation of mitochondrial K-ATP channels.

在大鼠缺血-再灌注模型中，检测缺血预处理、线粒体K-ATP通道开放剂尼可地尔和二氮嗪对减少梗死面积的影响。所有这些干预措施均显著缩小了梗死面积，表明线粒体K-ATP通道开放对于减轻缺血性损伤的重要性。梗死后3周采用左室压力-容积关系评价左室重构。线粒体K-ATP通道开放可减轻左室重构，重构程度与梗死面积相关。尼可地尔和二氮嗪开放线粒体K-ATP通道的机制不同，因为尼可地尔的作用被PKC抑制剂部分抑制，但二氮嗪的作用不受影响。蛋白质印迹法检测PKC亚型从胞浆向线粒体的转移。这表明尼可地尔将PKC ε和δ易位至线粒体组分，这可被PKC抑制剂抑制。此外，NO猝灭剂减少了这些亚型向线粒体组分的易位，表明尼可地尔的NO供体效应激活PKC ε和δ，随后与尼可地尔的直接开放效应协同激活线粒体K-ATP通道。通过免疫共沉淀法检测了线粒体中与PKC ε和δ结合的接头蛋白，发现了新的接头蛋白，它们可能在线粒体K-ATP通道的激活中起重要作用。