Plasmalogen Metabolism by iPLA2 in Ischemic Myocardium

缺血心肌中 iPLA2 的缩醛磷脂代谢

• 批准号: 6684148
• 负责人: JANE MCHOWAT
• 金额: $ 22.05万
• 依托单位: SAINT LOUIS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-12-01 至 2005-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6684148
• 关键词: G protein; arrhythmia; biological signal transduction; cardiac myocytes; coronary occlusion /thrombosis; enzyme activity; enzyme mechanism; heart electrical activity; heart metabolism; laboratory rabbit; lysophospholipids; mitogen activated protein kinase; myocardial ischemia /hypoxia; myocardium; phospholipase A2; plasmalogens; sarcolemma; thrombin; thromboembolism; vascular endothelium

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.

描述(申请人提供)：血栓性冠状动脉闭塞 已被证明在心肌梗死过程中直接导致心律失常 缺血提示从或与之相关的产品 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一种膜相关的， 钙非依赖性磷脂酶A2(IPLA2)导致选择性水解酶 花生四烯酸化血浆蛋白原磷脂和增加的产量 溶质膜胆碱(Lplc)和游离花生四烯酸。常氧灌流 LPLasC对兔心肌细胞动作电位的影响 和诱导的后去极化，这可能会导致 在缺血心脏启动心律失常的发生，提供了直接的联系 动脉粥样硬化血栓形成和心律失常之间的关系。此外，凝血酶 刺激内皮细胞可激活iPLA2和血管内皮细胞 胆碱溶血磷脂的释放。如果这些代谢物获得了 心肌细胞肌膜，也可能参与心律失常的发生。 拟议中的研究将检验的假设是凝血酶释放 冠脉内血栓引起的两亲性蓄积 缺血心肌中代谢产物溶质麦考林(LPlaC)的研究 产量的增加和分解代谢的减少。具体目标 用来检验这一假设的方法有： 1.确定LplC在体外的主要代谢途径 兔心室肌细胞。 2.测定胆碱溶血磷脂是否从 凝血酶刺激的内皮细胞可以进入心肌细胞 肌膜，它们可以促进心律失常的发生。 3.研究兔心室肌细胞磷脂酶A2亚型的特性。 促进非钙依赖的磷脂酶A2活性 4.确定参与细胞活化的信号转导途径 凝血酶刺激兔心室肌细胞后的iPLA2 常氧或低氧状态。 这些研究将提供有关心律失常如何发生的重要信息。 冠脉循环中的物质可能获得缺血心脏的途径 心肌细胞，参与iPLA2激活的生化途径和 心肌组织中LplC积聚的代谢途径 缺血症。我们的长期目标是确定代谢途径， 是新的治疗策略的合适靶点，以缓解 人类缺血性心脏病的发病率和死亡率。