AGING HEART--BASIS OF INCREASED ISCHEMIC/REFLOW INJURY

心脏老化——缺血/回流损伤增加的基础

• 批准号: 6169116
• 负责人: Charles Leslie Hoppel
• 金额: $ 88.99万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-08-15 至 2002-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6169116
• 关键词: aging; myocardial ischemia /hypoxia; oxidative stress; reperfusion

Our long-term goal is to develop a strategy to decrease the excess myocardial injury in elderly patients following an acute myocardial infarction. We have developed an approach to study this problem in the elderly Fischer 344 rat model. The isolated, buffer perfused elderly heart sustains greater injury after ischemia and reperfusion compared to the adult heart. At baseline, aging-defects in the mitochondrial electron transport chain occurs in only one population of heat mitochondria (interfibrillar) in elderly Fischer 344 rats. Following ischemia there is further damage to the interfibrillar mitochondria. We propose that aging- related defects in mitochondrial oxidative metabolism present at baseline in the elderly heart predispose to a subsequent increase in oxidative injury during ischemia and reperfusion compared to the adult heart, and that an excess of oxidative damage accounts for the increase in injury observed in the aging heart. The five interactive projects herein will use interventions that are designed to reduce the excess injury in the aging heat as tools to establish and intracellular sites of the increased damage that occurs in the aging heart during ischemia and reperfusion. We will test the hypothesis that the increase in Tumor Necrosis Factor alpha observed in aging tissue to the aging-related defect in complex II in interfibrillar mitochondria in the aging heart. We will determine if therapeutic intervention with a cell-permeable antioxidant N-2- mercaptopropionylglycine will protect the aging heart against the excess injury that occurs during ischemia and reperfusion, and will challenge the hypothesis that the tandem ischemic and aging-related defects in complex III in interfibrillar mitochondria increases damage in the aging heart via oxidative mechanisms. We will determine this structural basis of the ischemic defect in the Rieske iron-sulfur protein in complex III in interfibrillar mitochondria, and if the iron-sulfur protein sustains additional oxidative damage during reperfusion. We will test the hypothesis that oxidative damage to the enzyme carnitine palmitoyltransferase-I, the rate limiting step in fatty acid oxidation, occurs in interfibrillar mitochondria and leads to inappropriately increased fatty acid-oxidation and the accompanying deleterious consequences of excess fatty acid oxidation during reperfusion. We will challenge the hypothesis that a decrease in antioxidant defense mechanisms, including thioltransferase, in the aging heart results in increased oxidative injury.

我们的长期目标是制定一项策略以减少多余 急性心肌后，老年患者的心肌损伤 梗塞。我们已经开发了一种研究此问题的方法 老年Fischer 344大鼠模型。孤立的缓冲液灌注老年人心脏 与相比，缺血和再灌注后，遭受更大 成人心。在基线时，线粒体电子中的衰老缺失 运输链仅发生在一个热线粒体中 （Interfibillar）在老年Fischer 344只大鼠中。以下缺血有 对原纤维间线粒体的进一步损害。我们提出衰老 - 基线时存在的线粒体氧化代谢的相关缺陷 在老年人的心脏中，氧化剂易于增加 与成人心脏相比，缺血和再灌注期间受伤， 过量的氧化损伤造成了伤害的增加 在衰老的心脏中观察到。 这里的五个互动项目将使用干预措施 旨在减少衰老热量的多余伤害作为工具 建立和细胞内发生的损害增加 缺血和再灌注期间的衰老心脏。我们将测试 假设肿瘤坏死因子α在 衰老的组织到与衰老相关的缺陷中的衰老II中的衰老缺陷 衰老心脏中的线粒体。我们将确定是否治疗 干预细胞可渗透的抗氧化剂N-2- 膀胱丙基甘氨酸将保护衰老的心脏免受多余的 缺血和再灌注期间发生的伤害，并将挑战 假设复合物中的串联缺血性缺血和与衰老相关的缺陷 iii在纤维间线粒体中的III增加了衰老心脏的损害 氧化机制。我们将确定 rieske铁硫蛋白的缺血性缺陷在复合物III中 纤维间线粒体，如果铁硫蛋白持续 再灌注过程中的额外氧化损伤。我们将测试 假设氧化对酶肉碱的损害 棕榈酰转移酶I，脂肪酸氧化的速率限制步骤， 发生在原纤维线粒体中，导致不适当 增加脂肪酸氧化和随附有害的 再灌注过程中过量脂肪酸氧化的后果。我们将 挑战以下假设，即抗氧化防御的减少 衰老心脏中的机制，包括硫醇转移酶会导致 增加氧化损伤。