The relative order of mK(ATP) channels, free radicals and p38 MAPK in preconditioning's protective pathway in rat heart.
The relative order of mK(ATP) channels, free radicals and p38 MAPK in preconditioning's protective pathway in rat heart.
复制标题
DOI：
10.1016/s0008-6363(02)00452-2
复制
发表时间：
2002-08
影响因子：
10.8
通讯作者：
Yuankun Yue;Qining Qin;M. Cohen;J. Downey;S. Critz
中科院分区：
文献类型：
--
作者：
Yuankun Yue;Qining Qin;M. Cohen;J. Downey;S. Critz
目的：缺血预适应(PC)通过开放线粒体ATP依赖的钾通道(MKATP)、活性氧(ROS)，并可能激活p38丝裂原活化蛋白激酶(P38 MAPK)来减轻心肌梗死。然而，这些步骤的实际顺序目前仍存在争议。这项研究检查了甲奈二酮是否需要mKATP开放才能提供保护，甲奈二酮通过使线粒体产生ROS来保护细胞。此外，我们还测试了p38 MAPK激活剂茴香霉素的保护作用是否依赖于ROS的产生。方法和结果：分离的缓冲灌流大鼠心脏用甲奈二酮预处理，在局部缺血30min和再灌流120min后评估心肌梗死。甲奈酮以剂量依赖的方式减少梗塞，其EC50为270 nM。MKATP通道阻断剂2 0 0μM 5-羟基癸酸酯(5HD)不敏感美乃尼酮的心肌梗死保护作用，而二氮嗪和PC的保护作用可被5 HD阻断。大鼠心肌对缺血再灌注损伤有保护作用，这种保护作用可被p38MAPK抑制剂SB203580和自由基清除剂2-巯基丙酰甘氨酸(MPG)所阻断。结论：mKATP开放发生在线粒体ROS生成的上游。此外，茴香素的保护作用依赖于p38MAPK和ROS。
Objectives:Ischemic preconditioning (PC) reduces myocardial infarction by a mechanism that involves opening of mitochondrial ATP-dependent potassium channels (mKATP), reactive oxygen species (ROS), and possibly activation of p38 mitogen-activated protein kinase (p38 MAPK). The actual order of these steps, however, is a matter of current debate. This study examined whether protection afforded by menadione, which protects by causing mitochondria to produce ROS, requires mKATPopening. In addition, we tested whether protection from anisomycin, a p38 MAPK activator, is dependent on ROS production.Methods and Results:Isolated, buffer-perfused rat hearts were pretreated with menadione, and infarction was assessed after 30 min of regional ischemia and 120 min of reperfusion. Menadione reduced infarction in a dose-dependent manner with an EC50of 270 nM. Menadione's infarct-limiting effect was insensitive to 200 μM 5-hydroxydecanoate (5HD), an mKATPchannel blocker, whereas protection by diazoxide and PC were blocked by 5HD. Anisomycin caused hearts to resist infarction and this protective effect was abrogated by SB203580, a p38 MAPK inhibitor, and 2-mercaptopropionylglycine (MPG), a free radical scavenger.Conclusions:These results indicate that mKATPopening occurs upstream of mitochondrial ROS generation in the protective pathway. Furthermore, protection afforded by anisomycin was p38 MAPK- and ROS-dependent.