Suppression of ischemic myocardial injury by heat stress proteins

本研究最初计划检查热应激蛋白 HSP70 的诱导是否提供心脏保护作用，以及 HSP 诱导的保护作用（如果有的话）是否由 ATP 敏感 K 通道（KATP 通道）介导。热应激和短暂性缺血都会诱导 HSP70 的表达和轻微减弱的心肌顿抑。然而，HSP70 表达并没有增强抗梗塞耐受性。对心肌顿抑的心脏保护作用。因此，我们随后通过缺血前腺苷 A1 激活和缓激肽 B2 受体激活来评估 KATP 通道在心脏保护中的作用。蛋白激酶 C 抑制剂和线粒体 KATP 通道选择性阻断剂 5-羟基癸酸酯消除了 A1 和 B2 受体激活引起的梗塞面积限制。相反，肌膜KATP通道的选择性阻断剂HMR14098不影响A1受体和B2受体的缺血前刺激所产生的心脏保护作用。由于蛋白激酶 C 激活促进 KATP 通道的开放，目前的研究结果表明，线粒体 KATP 通道是 A1 受体介导和 B2 受体介导的心脏保护途径中蛋白激酶 C 下游的重要效应器。线粒体 KATP 通道在另一种心脏保护作用中的作用也得到了检验，即抑制 NaiD1 D1-D1 D1 交换器 1 型 (NHE1)。抑制该交换器不会直接激活分离的心肌细胞中的 KATP 通道。然而，5-羟基癸酸酯消除了 NHE1 抑制剂（即卡立泊利和乙基异丙基阿米洛利）的抗梗塞和抗昏迷作用，表明 NHE1 抑制需要线粒体 KATP 通道活性来提供保护。综上所述，线粒体 KATP 通道可能是心肌细胞中各种心脏保护信号下游的重要效应器。

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.