PLASMALOGEN-SELECTIVE PLA2 ACTIVATION IN ISCHEMIA

描述（改编自研究者摘要）：近期证据 表明冠状动脉内血栓的形成 缺血性心脏的心肌再生。 虽然该机制没有 已经确定，在凝块形成过程中凝血酶的产生增加可能 发挥重要作用。 急性闭塞性心肌缺血 血栓形成也伴随着加速的磷脂 导致溶血磷脂积聚在 肌膜，其直接有助于子宫内膜发生。 麦克霍瓦特医生和 他的同事发现用凝血酶刺激分离的肌细胞 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介导 （PLA 2）具有对醚连接的磷脂底物的明显偏好， 包括缩醛血浆。 他们最近发现缩醛磷脂是 离体兔心室肌细胞的主要磷脂成分 并且已经表明，膜相关的、缩醛磷脂选择性的 在缺氧过程中，分离的心肌细胞中的PLA 2增加。 因此，加速 缺氧时PLA 2催化的缩醛磷脂酶原催化剂和对缺氧的反应 凝血酶预期有助于两亲性的聚集， 溶血胞浆胆碱（LPlasC）产品，其具有惊人的程度， 与LPC结构相似。 此外，该小组的初步数据显示， 支持缺血期间LPlasC产生增加的结论， 导致电生理（EP）异常。 的 发现心肌细胞PLA 2活性的增加被完全阻断 通过钙非依赖性PLA 2的选择性抑制剂，从而定义了 研究钙非依赖性PLA 2作用的药理学策略 和伴随的溶血磷脂的产生在缺血性脑血管病的发病机制中 细胞损伤 待检验的假设是凝血酶有助于PLA 2活化 在缺氧的心肌细胞内，这导致LPlasC产生和EP增加 功能障碍 具体目的是：1）确定凝血酶在 PLA 2的激活和随后的溶血磷脂积累 分离的常氧和缺氧心肌细胞; 2）确定 参与LPlasC催化的代谢途径， 常氧和缺氧条件;和3）表征 外源性LPlasC在分离的心肌细胞中的电生理作用。 博士McHowat认为这些研究将提供重要的信息， 以帮助确定哪些代谢途径可以选择适当的 新的治疗策略的目标，旨在减少发病率 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.