MYOCARDIAL ISCHEMIC INJURY: MODIFICATION BY DRUG THERAPY

这个项目的目标是了解氧气的作用- 衍生自由基对心肌细胞缺血后损伤的影响 缺血再灌流。细胞的机制和特征 过氧化氢(H_2O_2)、超氧化物(O_2)和羟基的伤害 (哦。)心肌细胞培养中的自由基暴露及完好 将对心肌进行研究。此外，为了进一步 研究细胞损伤、O2和OH的位置。生产于 将对肌细胞进行研究。 当前提案的一个主要焦点是理解 过氧化氢和羟基自由基在血管紧张性心脏病发病机制中的作用 缺血介导的心肌细胞损伤。我们建议(1) H_2O_2是引起细胞损伤的重要氧代谢产物之一。 肌细胞通过·OH。产生和脂质过氧化。自.以来 H_2O_2的产生与O_2密切相关， 个别代谢物在细胞中的损伤尚不清楚。我们会 集中精力了解过氧化氢的作用(单独或 与O2结合)在细胞损伤中发挥作用；(2)我们将直接 调查一下OH。在缺血后再灌流期间产生， 将其与由此造成的损伤定量地关联起来，并研究 导致OH的细胞内机制。由过氧化氢生成。 我们还建议证明心肌细胞产生O2/OH。 在缺氧后的复氧过程中，这种产物主要是 与代谢异常和再灌流有关 线粒体呼吸作用。 超氧化物和羟基。在心脏和心肌细胞中产生的 细胞色素C法直接鉴定和测定高 加压液相色谱。细胞损伤将与 心功能、生化和数量细胞的改变 治疗干预前后的损害。实验 利用分离培养的心肌细胞的提议将使我们能够 研究特定氧自由基物种的直接作用和 细胞死亡过程中的进行性阶段 通过显微标记物可视化。对缺血性疾病的直接认识 特定氧自由基引起的细胞损伤将是 在新改进的姑息性药物开发中的重要作用 延缓或预防人体心肌损伤的策略。

The goal of this project is to understand the role of oxygen- derived radicals on cardiac cell injury during ischemia and post- ischemic reperfusion. Mechanisms and characteristics of cell injury by hydrogen peroxide (H2O2), superoxide (O2) and hydroxyl (OH.) radicals exposure in myocyte cultures and intact myocardium will be investigated. In addition, in order to further investigate the cell injury, sites of O2 and OH. production in myocytes will be studied. A major focus of the current proposal is to understand the role hydrogen peroxide and hydroxyl radical play in the pathogenesis of ischemia mediated cardiac cell injury. We are proposing that (1) H2O2 is one of important O2 metabolites in causing injury to myocytes through OH. production and lipid peroxidation. Since the generation of H2O2 is closely linked with O2, the damage by individual metabolites in the cell injury is not known. We will concentrate our efforts on understanding the role H2O2 (alone or in combination with O2) plays in cell damage; (2) we will directly investigate the OH. production during post-ischemic reperfusion, correlate it with resultant injury quantitatively and study the intracellular mechanism leading to OH. formation from H2O2. We also propose to demonstrate that myocytes produce O2/OH. during post-anoxic reoxygenation, and this production is primarily linked to metabolic abnormalities and the reperfusion of mitochondrial respiration. Superoxide and OH. generated in both hearts and myocytes will be directly identified and measured by cytochrome C assay and high pressure liquid chromatography. The cell injury will be correlated with heart function, altered biochemistry and quantitative cell damage before and after therapeutic interventions. Experiments proposed utilizing isolated cultured myocytes will allow us to study the direct effect of specific oxygen radical species and the progressive stages in the process of cell death as will be visualized by microscopic markers. Direct knowledge of ischemic cell injury caused by specific oxygen-derived radicals will be important in the development of new improved palliative strategies to retard or prevent myocardial injury in man.