MYOCARDIAL ISCHEMIC INJURY: MODIFICATION BY DRUG THERAPY

这个项目的目标是了解氧气的作用- 衍生自由基对心肌缺血及缺血后心肌细胞损伤的影响 缺血再灌注 细胞的机制和特征 过氧化氢（H_2O_2）、超氧化物（O_2）和羟基损伤 （OH.）自由基暴露在心肌细胞培养物和完整的 将研究心肌。 此外，为了进一步 观察细胞损伤、O2和OH的部位。生产 将研究肌细胞。 当前提案的一个主要重点是了解 过氧化氢和羟自由基在发病机制中的作用 缺血介导的心肌细胞损伤。 我们建议（1） H_2O_2是引起机体损伤的重要O_2代谢产物之一 通过OH.生产和脂质过氧化。 以来 H_2O_2的产生与O_2的产生密切相关， 细胞损伤中的单个代谢物是未知的。 我们将 集中我们的努力了解的作用H2 O2（单独或 与O2结合）在细胞损伤中起作用;（2）我们将直接 调查OH。在缺血后再灌注期间产生， 与致伤定量相关，研究 导致OH的细胞内机制。生成H2 O2。 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，这种生产主要是 与代谢异常和再灌注有关， 线粒体呼吸 超氧化物和OH。在心脏和肌细胞中产生的， 通过细胞色素C测定法直接鉴定和测量， 高压液相色谱法 细胞损伤将与 心脏功能改变，生化和定量细胞 治疗干预前后的损害。 实验 利用分离培养的心肌细胞， 研究特定氧自由基物种的直接作用和 细胞死亡过程中的渐进阶段， 通过显微镜标记可视化。 直接了解缺血性 由特定的氧衍生自由基引起的细胞损伤将是 在开发新的改进的姑息疗法中很重要 延缓或预防人类心肌损伤的策略。

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.