ANTIOXIDANTS AND REPERFUSION INJURY IN AGING HEART

衰老心脏中的抗氧化剂和再灌注损伤

• 批准号: 6098816
• 负责人: Edward J Lesnefsky
• 金额: $ 0.23万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-03-20 至 1999-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6098816
• 关键词: age difference; aging; animal old age; antioxidants; cardiolipins; electrospray ionization mass spectrometry; gas chromatography; hemodynamics; high performance liquid chromatography; juvenile animal; laboratory rat; lipid metabolism; metabolism disorder; mitochondria; myocardial ischemia /hypoxia; myocardium; nonhuman therapy evaluation; oxidative stress; perfusion; reperfusion; sulfur aminoacid

The morbidity and mortality of acute myocardial infarction remains dramatically elevated in elderly patients despite successful reperfusion treatments. The functional recovery of ischemic-reperfused tissue is impaired in elderly patients. We utilized Fischer 344 rat model of aging to study the increased injury present in the aging heart. Tissue damage was increased, and hemodynamic recovery decreased, in isolated buffer perfused hearts from 24 month elderly rats compared to 6 month adult controls. Elderly rats have a preexisting aging-related decrease in complex III and cytochrome oxidase activities that are selective to the interfibrillar population of cardiac mitochondria (IFM). Ischemia caused damage to complex III in IFM that was superimposed upon the aging defect. We propose that the baseline aging defects present in IFM act in concert with superimposed ischemic damage to augment oxidative injury during reperfusion, and that increased oxidative damage contributes to the excess injury observed in the aging heart. Oxidative reactions with mitochondrial membrane lipids will deplete cardiolipin, a phospholipid highly enriched in polyunsaturated acyl-residues, and alter the composition of cardiolipin as a signature of oxidative injury. To investigate the contributions of oxidative mechanisms to the excess injury that occurs during ischemia and reperfusion in the aging heart, we will determine if treatment with cell- permeable antioxidants such as N-2-mercaptopropionylglycine will ameliorate the excess damage observed in the aging heart during reperfusion. The targets of oxidative reperfusion injury in the aging heart in mitochondria will be assessed by measuring specific endpoints of oxidative damage including the depletion and oxidative alteration of cardiolipin. The decreased tolerance of the aging heart to ischemia and reperfusion represent a novel situation in which to explore the contributions of aging-related metabolic defects acting in concert with the superimposed metabolic stress of ischemia to further impair recovery of the aging heart. This experimental approach will delineate the targets of oxidative injury during ischemia and reperfusion in the aging heart and contribute to the design of mechanism-based adjunctive treatment strategies to enhance outcome in the high-risk elderly patient suffering from acute myocardial infarction.

急性心肌梗死的发病率和死亡率仍居高不下 尽管成功再灌注，老年患者的血压仍显着升高 治疗。缺血再灌注组织的功能恢复是 老年患者受损。我们利用 Fischer 344 大鼠衰老模型 研究衰老心脏中存在的增加的损伤。组织损伤 在隔离缓冲液中增加，血流动力学恢复降低 24 个月龄老年大鼠与 6 个月成年大鼠的灌注心脏 控制。老年大鼠先前存在与衰老相关的 复合体 III 和细胞色素氧化酶活性对 心脏线粒体（IFM）的纤维间群体。缺血引起 IFM 中复合物 III 的损伤叠加在老化缺陷上。 我们建议 IFM 中存在的基线老化缺陷协同作用 叠加缺血性损伤以增强氧化损伤 再灌注，氧化损伤的增加导致过度 在衰老的心脏中观察到的损伤。与线粒体的氧化反应 膜脂会消耗心磷脂（一种高度浓缩的磷脂） 多不饱和酰基残基，并改变心磷脂的组成 作为氧化损伤的标志。调查贡献 缺血期间发生的过度损伤的氧化机制 老化心脏的再灌注，我们将确定是否使用细胞治疗 渗透性抗氧化剂，例如 N-2-巯基丙酰甘氨酸 改善老化心脏在老化过程中观察到的过度损伤 再灌注。衰老过程中氧化再灌注损伤的靶点 线粒体中的心脏将通过测量特定终点来评估 氧化损伤，包括消耗和氧化改变 心磷脂。衰老的心脏对缺血的耐受力下降 再灌注代表了一种新的情况，在这种情况下探索 与衰老相关的代谢缺陷协同作用的贡献 缺血叠加的代谢应激进一步损害恢复 属于衰老的心脏。这种实验方法将描绘目标 衰老心脏缺血和再灌注过程中氧化损伤的影响 有助于设计基于机制的辅助治疗 提高高危老年患者治疗效果的策略 来自急性心肌梗塞。