PLASMALOGEN-SELECTIVE PLA2 ACTIVATION IN ISCHEMIA

描述(改编自《调查者摘要》)：最新证据 表明冠状动脉内血栓的形成直接导致 导致缺血心脏发生心律失常。尽管这一机制并没有 在血栓形成过程中增加凝血酶的产生可能 发挥重要作用。急性闭塞所致心肌缺血 血栓形成还伴随着加速的磷脂。 分解代谢导致溶血磷脂在体内的积累 肌膜是导致心律失常的直接原因。McHowat博士和 同事们发现凝血酶对分离的心肌细胞的刺激 结果导致溶血磷脂酰胆碱(LPC)的产生增加 通过激活一种新的钙非依赖性磷脂酶A2来介导 (PLA2)对乙醚连接的磷脂底物有明显的偏好， 包括浆原菌。他们最近鉴定出血浆原细菌是 分离的兔心肌细胞的主要磷脂成分 并表明膜相关的、选择性的纤溶酶原的活性 在低氧条件下，心肌细胞内PLA2水平升高。因此，加速了 低氧时PLA2催化的纤溶酶原分解代谢及对 凝血酶有望促进两亲性物质的积累 溶质膜胆碱(Lplc)产品，其具有惊人的 与LPC的结构相似。此外，来自该小组的初步数据 支持这一结论，即LplC的产生在缺血和缺氧期间增加 导致电生理(EP)异常的产生。这个 心肌细胞PLA2活性的增加被发现完全被阻断 通过选择性地抑制非钙依赖的PLA2，从而定义 研究钙非依赖性磷脂酶A2作用的药理学策略 并伴随着溶血磷脂的产生在缺血性脑损伤的发病机制中的作用 细胞损伤。 需要检验的假设是凝血酶有助于PLA2的激活 在缺氧性心肌细胞内，导致LplC产生和EP增加 功能障碍。具体目的是：1)确定凝血酶在 磷脂酶A2激活及随后的溶血磷脂蓄积 分离常氧和低氧心肌细胞；2)测定 两种情况下参与Lplc分解代谢的代谢途径 常氧和低氧条件；以及3)表征 外源性LplC对心肌细胞的电生理效应。 麦克豪特博士认为，这些研究将提供重要的信息 以帮助确定可以适当地选择哪些代谢途径 为新的治疗策略提供目标，旨在减少 急性心肌缺血时的心律失常。

DESCRIPTION (Adapted from Investigator's Abstract): Recent evidence indicates that formation of an intracoronary thrombus contributes directly to arrhythmogenesis in the ischemic heart. Although the mechanism has not been established, increased production of thrombin during clot formation may play an important role. Myocardial ischemia resulting from acute occlusive thrombus formation is also accompanied by accelerated phospholipid catabolism resulting in the accumulation of lysophospholipids in the sarcolemma which directly contributes to arrhythmogenesis. Dr. McHowat and colleagues have found that stimulation of isolated myocytes with thrombin results in increased lysophosphatidylcholine (LPC) production which appears to be mediated by activation of a novel calcium-independent phospholipase A2 (PLA2) with a distinct preference for ether-linked phospholipid substrates, including plasmalogens. They have recently identified plasmalogens as principal phospholipid constituents in isolated rabbit ventricular myocytes and have shown that activity of membrane-associated, plasmalogen-selective PLA2 in isolated myocytes is increased during hypoxia. Thus, accelerated PLA2-catalyzed plasmalogen catabolism during hypoxia and in response to thrombin is expected to contribute to accumulation of amphiphilic lysoplasmenylcholine (LPlasC) products, which bear a striking degree of structural similarity to LPC. In addition, preliminary data from this group support the conclusion that LPlasC production increases during ischemia and contributes to production of electrophysiologic (EP) abnormalities. The increase in cardiac myocyte PLA2 activity was found to be completely blocked by a selective inhibitor of calcium-independent PLA2, thereby defining a pharmacologic strategy to investigate the role of calcium-independent PLA2 and accompanying lysophospholipid production in the pathogenesis of ischemic cell injury. The hypothesis to be tested is that thrombin contributes to PLA2 activation within hypoxic myocytes which leads to increased LPlasC production and EP dysfunction. The Specific Aims are: 1) to define the role of thrombin in the activation of PLA2 and subsequent lysophospholipid accumulation in isolated normoxic and hypoxic cardiac myocytes; 2) to determine the metabolic pathways that participate in the catabolism of LPlasC under both normoxic and hypoxic conditions; and 3) to characterize the electrophysiologic effects of exogenous LPlasC in isolated cardiac myocytes. Dr. McHowat suggests that these studies will provide important information to help determine which metabolic pathways could be selected as appropriate targets for novel therapeutic strategies aimed at reducing the incidence of arrhythmias in the setting of acute myocardial ischemia.