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Suppression of ischemic myocardial injury by heat stress proteins

热应激蛋白抑制缺血性心肌损伤

基本信息

批准号：
08670812
负责人：
MIURA Tetsuji
金额：
$ 1.41万
依托单位：
Sapporo Medical University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
1996
资助国家：
日本
起止时间：
1996 至 1998
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-08670812/
关键词：
stress proteins adenosine myocardial ischemia K channels mitochondria 心筋梗塞虚血心筋スタニング

项目摘要

The present study initially planed to examine whether induction of heat stress proteins, HSP70's, afford cardioprotection and whether the HSP-induced protection, if any, is mediated by ATP-sensitive K channels (KATP channels). Both heat stress and a transient ischemia induced expression of HSP70 and slight attenuated myocardial stunning. However, anti-infarct tolerance was not enhanced by HSP70 expression. Furthermore, there was a dissociation between the expression of HSP70 and the cardioprotection against myocardial stunning. Thus, we then assessed the role of KATP channels in cardioprotection by pre-ischemic activation of adenosine A1 and bradykinin B2 receptor activation. Infarct size limitation by A1 and B2 receptor activation was abolished by protein kinase C inhibitors and by a selective blocker of mitochondrial KATP channels, 5-hydroxydecanoate. In contrast, a selective blocker of sarcolemmal KATP channels, HMRl4098, did not affect cardioprotection by pre-ischemic stimulation of A1 and that by B2 receptors. Since protein kinase C activation facilitates opening of KATP channels, the present findings indicate that the mitochondrial KATP channel is an important effector downstream of protein kinase C in the A1 receptor-mediated and B2 receptor-mediated pathways of cardioprotection. The role of the mitochondrial KATP channel was also examined in another type of cardioprotection, inhibition of NaィイD1+ィエD1-HィイD1+ィエD1 exchanger type 1 (NHE1). Inhibition of this exchanger does not directly activate KATP channels in isolated cardiomyocytes. However, 5-hydroxydecanoate abolished anti-infarct and anti-stunning effects of NHE1 inhibitors (i.e., cariporide and ethyl-isopropyl amiloride), indicating requirement of mitochondrial KATP channel activity for protection by NHE1 inhibition. Taken together, the mitochondrial KATP channel may be an important effector downstream of various cardioprotective signals in the cardiomyocyte.

本研究最初计划研究热应激蛋白S的诱导是否提供心脏保护，以及热应激诱导的保护是否由三磷酸腺苷敏感的钾通道(KATP通道)介导。热应激和短暂缺血均可诱导HSP70的表达，并可轻微减轻心肌顿抑。然而，HSP70的表达并不能提高抗心肌梗死的耐受性。此外，HSP70的表达与抗心肌顿抑的心肌保护作用无关。因此，我们通过缺血前激活腺苷A1和激活缓激肽B2受体来评估KATP通道在心脏保护中的作用。A1和B2受体的激活可被蛋白激酶C抑制剂和线粒体KATP通道的选择性阻断剂5-羟基癸酸所取消。相反，肌膜KATP通道的选择性阻断剂HMR14098不影响缺血前刺激A1和B2受体对心肌的保护作用。由于蛋白激酶C的激活促进了KATP通道的开放，本研究结果表明，在A1受体和B2受体介导的心脏保护途径中，线粒体KATP通道是蛋白激酶C下游的重要效应器。线粒体KATP通道在另一种类型的心脏保护中的作用也被研究，即抑制NaィイD1+ィエD1-HィイD1+ィエD1交换器1(NHE1)。抑制这种交换器并不能直接激活心肌细胞上的KATP通道。然而，5-羟基癸酸取消了NHE1抑制剂(即卡利波胺和乙基异丙基阿米洛利)的抗脑梗塞和抗顿抑作用，表明NHE1抑制需要线粒体KATP通道活性的保护。综上所述，线粒体KATP通道可能是心肌细胞中各种心肌保护信号下游的重要效应器。