Plasmalogen Metabolism by iPLA2 in Ischemic Myocardium

描述（由申请人提供）：血栓性冠状动脉闭塞 已被证明直接有助于心肌梗死 缺血表明，释放或相关的产品， 冠状动脉内血栓可能直接或间接影响 缺血心肌细胞的电生理特性。凝血酶 刺激兔心室肌细胞激活膜相关的， 钙非依赖性磷脂酶A2（iPLA 2）导致选择性水解 花生四烯酸化的缩醛磷脂和增加的 溶血胞浆胆碱（LPlasC）和游离花生四烯酸。常氧灌注 LPLasC致兔心室肌细胞动作电位紊乱 和诱导的后去极化，这可能有助于 在缺血性心脏中启动血管生成， 动脉粥样硬化血栓形成和血栓形成之间的联系。此外，凝血酶 内皮细胞的刺激导致iPLA 2的激活， 释放胆碱溶血磷脂。如果这些代谢物能够进入 心室肌细胞肌膜，它们也可能有助于心肌发生。 拟议研究要检验的假设是凝血酶释放 导致两亲性的 结果，缺血心肌中的代谢物溶血质胆碱（LPlasC） 增加产量和减少卡路里。具体目标 旨在检验这一假设的是： 1.为了阐明LPlasC代谢的主要途径， 兔心室肌细胞 2.为了确定是否胆碱溶血磷脂释放从 凝血酶刺激的内皮细胞可以进入心肌细胞， 肌膜，它们可能有助于子宫内膜生成。 3.为了表征兔心室肌细胞中的PLA2亚型， 促进钙非依赖性PLA2活性 4.为了确定参与激活的信号转导途径， 凝血酶刺激下兔心室肌细胞的iPLA 2 常氧或缺氧条件下。 这些研究将提供重要的信息， 冠状循环中的物质可以进入缺血性心脏， 心肌细胞，参与iPLA 2激活的生化途径和 代谢途径负责LPlasC积累在心肌 缺血我们的长期目标是确定 是新的治疗策略的合适靶点， 人类缺血性心脏病的发病率和死亡率。

DESCRIPTION (provided by applicant): Thrombotic coronary artery occlusion has been demonstrated to contribute directly to arrhythmogenesis during myocardial ischemia suggesting that products released from or associated with an intracoronary thrombus may directly or indirectly influence the electrophysiologic properties of ischemic cardiac myocytes. Thrombin stimulation of rabbit ventricular myocytes activates a membrane-associated, Ca-independent phospholipase A2 (iPLA2) resulting in selective hydrolysis of arachidonylated plasmalogen phospholipids and increased production of lysoplasmenylcholine (LPlasC) and free arachidonic acid. Perfusion of normoxic rabbit ventricular myocytes with LPLasC produced action potential derangements and induced afterdepolarizations which would likely contribute to the initiation of arrhythmogenesis in the ischemic heart, providing a direct link between atherothrombosis and arrhythmogenesis. Additionally, thrombin stimulation of endothelial cells results in the activation of iPLA2 and the release of choline lysophospholipids. If these metabolites gain access to the ventricular myocyte sarcolemma, they may also contribute to arrhythmogenesis. The hypothesis to be tested by the proposed studies is that thrombin released from an intracoronary thrombus causes accumulation of the amphiphilic metabolite lysoplasmenyicholine (LPlasC) in the ischemic myocardium as a result of both increased production and decreased catabolism. The specific aims designed to test this hypothesis are: 1. To delineate the principal pathways for metabolism of LPlasC in isolated rabbit ventricular myocytes. 2. To determine whether choline lysophospholipids released from thrombin-stimulated endothelial cells can gain access to the cardiac myocyte sarcolemma where they could contribute to arrhythmogenesis. 3. To characterize the PLA2 isoforms in rabbit ventricular myocytes that contribute to Ca-independent PLA2 activity 4. To determine the signal transduction pathways involved in the activation of iPLA2 following thrombin stimulation of rabbit ventricular myocytes under normoxic or hypoxic conditions. These studies will provide important information regarding how arrhythmogenic substances in the coronary circulation may gain access to ischemic cardiac myocytes, the biochemical pathways involved in iPLA2 activation and the metabolic pathways responsible for LPlasC accumulation during myocardial ischemia. Our long-term objectives are to determine the metabolic pathways that are appropriate targets for novel therapeutic strategies to alleviate the morbidity and mortality of ischemic heart disease in man.