ANTIOXIDANTS AND REPERFUSION INJURY IN AGING HEART

急性心肌梗死的发病率和死亡率仍然是 尽管成功再灌注，老年患者的血压仍显著升高 治疗。缺血-再灌注组织的功能恢复是 在老年患者中受损。采用Fischer 344大鼠衰老模型 来研究衰老的心脏中损伤的增加组织损伤 在隔离缓冲液中， 与6个月成年大鼠相比，24个月老年大鼠的灌注心脏 对照老年大鼠的大脑皮层中存在与衰老相关的减少， 复合物III和细胞色素氧化酶的活性是选择性的， 心肌线粒体原纤维间群（IFM）。缺血引起的 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 同时伴有缺血性损伤， 再灌注，增加的氧化损伤有助于过度 在衰老的心脏中观察到的损伤。与线粒体的氧化反应 膜脂将消耗心磷脂，一种高度富集的磷脂 在多不饱和酰基残基，并改变心磷脂的组成 作为氧化损伤的标志调查的贡献 氧化机制对缺血期间发生的过度损伤， 再灌注在老化的心脏，我们将确定是否与细胞治疗- 渗透性抗氧化剂如N-2-巯基丙酰甘氨酸将 改善在老化心脏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以下特定终点来评估： 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性降低， 再灌注代表了一种新的情况，在这种情况下， 与衰老相关的代谢缺陷的贡献 缺血的叠加代谢应激进一步损害恢复 衰老的心脏这种实验方法将描绘出目标 衰老心脏缺血和再灌注期间氧化损伤的研究， 有助于设计基于机制的预防性治疗 提高高危老年患者预后的策略 急性心肌梗塞

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.