ANTIOXIDANTS AND REPERFUSION INJURY IN AGING HEART

急性心肌梗死的发病率和死亡率 老年患者尽管再通成功，但仍显著升高 治疗。缺血再灌流组织的功能恢复 在老年患者中受损。我们利用Fischer 344大鼠衰老模型 目的：研究衰老心脏中损伤程度的增加。组织损伤 在隔离缓冲液中增加，血流动力学恢复率降低 24月龄老年大鼠与6月龄成年大鼠心脏灌流的比较 控制。老年大鼠先前存在与衰老相关的减少 络合物III和细胞色素氧化酶活性对 心肌线粒体纤维间质群(IFM)。缺血所致 对IFM中叠加在老化缺陷上的复合体III的损坏。 我们认为IFM中存在的基线老化缺陷是一致的 叠加缺血损伤以增强氧化损伤 再灌注，而氧化损伤的增加导致了过量 在老化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，这是一种高度浓缩的磷脂 多不饱和酰基残基中，并改变心磷脂的组成 作为氧化损伤的标志。调查……的贡献 脑缺血时过度损伤的氧化机制 在老化的心脏中进行再灌注，我们将确定是否用细胞- 渗透性抗氧化剂，如N-2-巯基丙酰甘氨酸 改善心脏老化过程中观察到的过度损伤 再灌流。氧化再灌注损伤在衰老中的作用靶点 线粒体中的心脏将通过测量特定的终点进行评估 氧化损伤，包括细胞的耗竭和氧化改变 心磷脂。老化心脏对缺血和缺氧的耐受性降低 再灌注代表了一种新的情况，在这种情况下可以探索 与衰老相关的代谢缺陷的贡献与 进一步损害恢复的缺血叠加代谢应激 老化的心脏。这一实验方法将勾勒出目标 老年心脏缺血再灌流过程中氧化损伤的变化 有助于基于机制的辅助治疗的设计 提高高危老年患者预后的策略 死于急性心肌梗塞。

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.