Plasmalogen Metabolism by iPLA2 in Ischemic Myocardium

描述（由申请人提供）：血栓性冠状动脉闭塞

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.