Inhibition of mitochondrial calcium-independent phospholipase A2 (iPLA2) attenuates mitochondrial phospholipid loss and is cardioprotective.
Inhibition of mitochondrial calcium-independent phospholipase A2 (iPLA2) attenuates mitochondrial phospholipid loss and is cardioprotective.
复制标题
DOI：
10.1042/bj3620023
复制
发表时间：
2002-02
期刊：
影响因子：
--
通讯作者：
Scott D Williams;R. Gottlieb
中科院分区：
文献类型：
--
作者：
Scott D Williams;R. Gottlieb
钙非依赖性磷脂酶A(2)是存在于心肌中的主要磷脂酶A(2)，在心肌缺血再灌注(I/R)过程中，膜相关磷脂酶A(2)活性迅速升高，提示其在急性心肌梗死中的病理生理作用。因此，我们研究了从兰登多夫灌流的成年兔心脏制备的线粒体部分中的iPLA2。我们的研究表明，ipla(2)β存在于兔心脏线粒体内膜上，在缺血、I/R或预适应过程中没有明显的移位。线粒体相关的iPLA(2)具有催化活性，在缺血、I/R和预适应后，所测到的iPLA2活性分别是对照心脏线粒体测得的iPLA2活性的2倍、3倍和2.5倍。线粒体磷脂是维持细胞器有序结构和功能所必需的。电喷雾电离质谱仪显示，I/R后，心肌中的磷脂酰胆碱和磷脂酰乙醇胺甘油磷脂种类迅速减少，而iPLA2的特异性抑制剂溴烯醇内酯(BEL)可部分缓解I/R引起的心肌损伤。用10微米BEL对I/R心脏进行预处理，可显著减少心肌梗死面积，几乎达到持续灌流心脏的水平，而且只有在缺血前给予BEL才能起到心脏保护作用。BEL对心肌的保护作用可被同时灌流100微米5-羟基癸酸所逆转，提示BEL介导的线粒体K(ATP)通道参与了BEL介导的心肌I/R保护作用。综上所述，这些数据强烈暗示线粒体相关的iPLA2(2)参与了心肌I/R损伤的信号转导。
Calcium-independent phospholipase A(2) (iPLA(2)) is the predominant phospholipase A(2) present in myocardium, and its pathophysiological role in acute myocardial infarction has been suggested by the rapid increase in membrane-associated iPLA(2) activity during myocardial ischaemia and reperfusion (I/R). We therefore examined iPLA(2) in mitochondrial fractions prepared from Langendorff-perfused adult rabbit hearts. Our studies indicate that iPLA(2)beta is present in rabbit heart mitochondrial inner membranes with no apparent translocation during ischaemia, I/R or preconditioning. Mitochondrion-associated iPLA(2) was catalytically competent and exhibited 2-, 3- and 2.5-fold increases in measured iPLA(2) activity following ischaemia, I/R and preconditioning, respectively, when compared with the activity of iPLA(2) measured in mitochondria from control hearts. Mitochondrial phospholipids are essential for maintaining the ordered structure and function of the organelle. I/R resulted in a rapid overall decrease in phosphatidylcholine and phosphatidylethanolamine glycerophospholipid species, as determined by electrospray ionization MS, that was partially alleviated by pretreatment of hearts with the iPLA(2)-specific inhibitor, bromoenol lactone (BEL). Pretreatment of I/R hearts with 10 microM BEL significantly reduced the infarct size almost to that of continuously perfused hearts and was cardioprotective only when administered prior to ischaemia. Cardioprotection by BEL was reversed by the simultaneous perfusion of 100 microM 5-hydroxydecanoate, implicating the mitochondrial K(ATP) channel in BEL-mediated protection from I/R. Preconditioning also significantly reduced the infarct size in response to I/R but protection was lost by concurrent perfusion of 10 microM arachidonic acid. Taken together, these data strongly implicate mitochondria-associated iPLA(2) in the signal transduction of myocardial I/R injury.