MITOCHONDRIA INCREASE OXIDATIVE INJURY IN AGING HEART

老年患者的发病率和死亡率显著增加。 在急性心肌梗死后。尽管溶栓成功 90分钟时，75岁以上的急性脑梗塞患者 T-PA和链激酶类溶栓试验的全球应用 与年轻患者相比，治疗持续了更大的梗塞，并 大大降低了梗死区收缩功能的恢复。 我们发现，扩大的心肌损伤也发生在孤立的， 老年24月龄Fischer 344大鼠的缓冲液灌流心脏 缺血和再灌注后与6个月后心脏的比较 费舍尔成年后，支撑源的心肌损伤增加。 老化的心脏降低了已形成的压力的恢复并增加了 释放组织损伤的酶标记物。因此，无论是老年患者还是 从衰老动物模型中分离出来的心脏可以维持更长的时间 严重缺血再灌流成功后的心肌损害 与成人对照组相比。 我们假设缺血线粒体的进化速度更快 损伤会增加老化心脏的损伤。我们 提出更大的线粒体损伤会增加线粒体 产生极具活性和破坏性的羟基自由基(OH) 再灌流。我们将比较两种情况下缺血性损伤的演变。 心肌线粒体的独立群体(肌膜下和 纤维间)取自隔离的、缓冲灌流的成人和老年人 费舍尔344只老鼠心脏。分离株产氢能力的研究 将通过以下方法测量缺血老年人和成人心脏的线粒体 水杨酸羟基化法。我们认为增加的缺血 老年心脏的电子传递损伤将导致更大的OH 制作。线粒体的抗氧化活性将在事先进行测量 在缺血前后，确定抗氧化剂防御能力是否降低 会导致老化心脏的损伤。我们将确定是否 再灌流期间线粒体和心肌细胞损伤增加 衰老的心脏，以及是否可以通过羟基干预来减少它 清道夫。电子传递损伤在OH中的致病作用 生产将通过比较再灌注损伤的程度和 哦，生产在每个时代的心脏里，再灌流在存在和 缺乏线粒体电子传递的抑制剂。这些研究 将确定老化的心脏是否会受到 线粒体衍生氧自由基产生减少的背景 线粒体抗氧化防御，放大氧化损伤 再灌流过程中线粒体和心肌细胞。过度氧化损伤 可能会导致观察到的额外损害和恢复减少 在老化的心脏实验和临床情况下。一个 对衰老心脏意志力过度损伤机制的认识 需要设计辅助治疗策略，以补充 高危老年患者溶栓成功的益处。 他的研究重点是氧化损伤的机制。 老化心脏的缺血和再灌流，因为氧化损伤是 可能在老化的组织中增强，氧化机制有 鉴于#年死亡率的增加，潜在的临床重要性 老年心肌梗死患者。

Elderly patients have a markedly increased morbidity and mortality following acute myocardial infarction. Despite successful thrombolysis at 90 minutes, patients older than age 75 with acute infarction in the Global Utilization of t-PA and Streptokinase Trial of thrombolytic therapy sustained larger infarcts compared to younger patients, and had greatly reduced recovery of contractile function in the infarct zone. We found that augmented myocardial injury also occurred in isolated, buffer perfused hearts obtained from elderly 24 month Fischer 344 rats following ischemia and reperfusion compared to hearts from 6 month Fischer adults, supporting a myocardial source of the increased damage. Aging hearts had decreased recovery of developed pressure and increased release of enzyme markers of tissue injury. Thus, both elderly patients and isolated hearts from an animal model of aging sustain greater myocardial damage following successful reperfusion of severe ischemia compared to adult controls. We hypothesize that a more rapid evolution of ischemic mitochondrial injury contributes to the increased damage in the aging heart. We propose that greater mitochondrial injury increases mitochondrial production of the very reactive and damaging hydroxyl radical (OH) during reperfusion. We will compare the evolution of ischemic injury in the two independent populations of cardiac mitochondria (subsarcolemmal and interfibrillar) obtained from isolated, buffer perfused adult and elderly Fischer 344 rat hearts. The OH-generating capability of isolated mitochondria from ischemic elderly and adult hearts will be measured by the salicylate hydroxylation method. We propose that increased ischemic electron transport damage in the elderly heart will lead to greater OH production. Mitochondrial antioxidant activity will be measured prior to and following ischemia, to determine if reduced antioxidant defenses contribute to injury in the aging heart. We will determine if mitochondrial and myocyte injury during reperfusion is increased in the elderly heart, and if it can be reduced by intervention with a OH scavenger. The causative role of electron transport damage in OH production will tested by comparing the extent of reperfusion injury and OH production in hearts of each age reperfused in the presence and absence of inhibitors of mitochondrial electron transport. These studies will determine if the aging heart is subject to increased mitochondrially-derived oxyradical production in the setting of decreased mitochondrial antioxidant defenses, amplifying oxidative injury to mitochondria and myocytes during reperfusion. Excess oxidative injury could contribute to the additional damage and decreased recovery observed in the aging heart in both experimental and clinical situations. An understanding of the mechanisms of excess injury in the aging heart will be required to design adjunctive treatment strategies to supplement the benefit of successful thrombolysis in the higher risk elderly patient. The PI has focused his study of the mechanisms of oxidative injury during ischemia and reperfusion on the aging heart, since oxidative injury is likely to be enhanced in aging tissue, and oxidative mechanisms have potential clinical importance in view of the increased mortality in elderly patients with myocardial infarction.