Role of protein kinase C in mitochondrial KATP channel-mediated protection against Ca2+ overload injury in rat myocardium.
Role of protein kinase C in mitochondrial KATP channel-mediated protection against Ca2+ overload injury in rat myocardium.
复制标题
蛋白激酶 C 在线粒体 KATP 通道介导的大鼠心肌 Ca2 超载损伤保护中的作用。
DOI：
10.1161/01.res.84.10.1156
复制
发表时间：
1999
影响因子：
20.1
通讯作者：
Ashraf,M
中科院分区：
文献类型：
--
作者：
Wang,Y;Ashraf,M
-越来越多的证据表明，atp敏感的线粒体钾通道（MitoKATPchannel）是心脏抗缺血保护的主要因素。考虑到线粒体在心肌细胞中的重要性，我们测试了MitoKATPchannel二氮氧化物的强效和特异性打开剂是否能减轻与Ca2+过载相关的致命损伤。本研究的具体目的是测试二氮氧化物的保护作用是否由mitokatp通道介导；二氮氧化合物是否模拟Ca2+预处理的作用；以及二氮氧化物是否通过蛋白激酶C （PKC）信号通路减少Ca2+悖论（PD）损伤。langendorff灌注的大鼠心脏受到Ca2+PD（10分钟的Ca2+耗尽，然后10分钟的Ca2+充满）。评估MitoKATPchannel和其他干预措施对Ca2+PD下心脏功能、生化和病理变化的影响。用80 μmol/L二氮氧化合物处理心脏，Ca2+PD后左室舒张末压和冠状动脉血流明显保持；乳酸脱氢酶释放峰也显著降低，但ATP含量减少较少。与未处理的Ca2+PD心脏相比，二氮氧化物处理心脏的细胞结构得到了很好的保存，包括线粒体和嵌入盘。二氮氧化物对Ca2+PD损伤的有益作用与在Ca2+PD前进行Ca2+预处理或用12-肉豆蔻酸13-乙酸磷预处理的心脏相似。在二氮氧化物预处理过程中，添加特异性MitoKATPchannel抑制剂5-羟基癸酸钠或PKC抑制剂chelerythrine chloride完全消除了二氮氧化物对Ca2+PD的有益作用。通过维拉帕米或硝苯地平抑制l型Ca2+通道来阻断二氮氧化合物治疗期间Ca2+进入也完全逆转了二氮氧化合物对Ca2+PD的有益作用。PKC-δ易位于二氮氧化物预处理的心肌细胞的线粒体、插层盘和细胞核，PKC-α和PKC-ε分别易位于肌膜和插层盘。本研究提示MitoKATPchannel的作用是通过pkc介导的信号通路介导的。
—Growing evidence exists that ATP-sensitive mitochondrial potassium channels (MitoKATPchannel) are a major contributor to the cardiac protection against ischemia. Given the importance of mitochondria in the cardiac cell, we tested whether the potent and specific opener of the MitoKATPchannel diazoxide attenuates the lethal injury associated with Ca2+overload. The specific aims of this study were to test whether protection by diazoxide is mediated by MitoKATPchannels; whether diazoxide mimics the effects of Ca2+preconditioning; and whether diazoxide reduces Ca2+paradox (PD) injury via protein kinase C (PKC) signaling pathways. Langendorff-perfused rat hearts were subjected to the Ca2+PD (10 minutes of Ca2+depletion followed by 10 minutes of Ca2+repletion). The effects of the MitoKATPchannel and other interventions on functional, biochemical, and pathological changes in hearts subjected to Ca2+PD were assessed. In hearts treated with 80 μmol/L diazoxide, left ventricular end-diastolic pressure and coronary flow were significantly preserved after Ca2+PD; peak lactate dehydrogenase release was also significantly decreased, although ATP content was less depleted. The cellular structures were well preserved, including mitochondria and intercalated disks in diazoxide-treated hearts compared with nontreated Ca2+PD hearts. The salutary effects of diazoxide on the Ca2+PD injury were similar to those in hearts that underwent Ca2+preconditioning or pretreatment with phorbol 12-myristate 13-acetate before Ca2+PD. The addition of sodium 5-hydroxydecanoate, a specific MitoKATPchannel inhibitor, or chelerythrine chloride, a PKC inhibitor, during diazoxide pretreatment completely abolished the beneficial effects of diazoxide on the Ca2+PD. Blockade of Ca2+entry during diazoxide treatment by inhibiting L-type Ca2+channel with verapamil or nifedipine also completely reversed the beneficial effects of diazoxide on the Ca2+PD. PKC-δ was translocated to the mitochondria, intercalated disks, and nuclei of myocytes in diazoxide-pretreated hearts, and PKC-α and PKC-ε were translocated to sarcolemma and intercalated disks, respectively. This study suggests that the effect of the MitoKATPchannel is mediated by PKC-mediated signaling pathway.