MITOCHONDRIAL FUNCTION--AGE, GENDER, AND DISEASE EFFECTS

绝经后妇女心肌梗死后预后较差 心肌梗死(MI)多于男性。对更大事物的部分解释 妇女的死亡率和发病率是失去了 雌激素或性别差异在年龄、同时患有的疾病或 治疗。人们对看似合理的问题给予了极少的关注 性别影响基本生活的另一种解释 心肌梗死的病理生理转归，特别是 心脏抗氧化防御系统(ADS)。ADS提供了至关重要的 对释放的活性氧物种(ROS)的保护 在心肌梗死的有害缺血和再灌注(I/R)期间。 线粒体是ROS少量泄漏的主要靶点 在正常的氧化磷酸化过程中和在 I/R 据报道，线粒体ADS在男性心脏中减少 啮齿动物的衰老。我的初步研究表明，衰老 对雌性大鼠心肌线粒体ADS影响不大。 为心脏反应的性别差异提供了强有力的证据 广告致衰老。拟议的研究将检验这样一个假设，即性别、 年龄和疾病是易感性的相互依存的变量 心肌线粒体对ROS损伤的保护作用。甲亢是一种疾病 用于研究，因为据报道它会增加ROS的氧化应激 心肌线粒体ADS状态改变与渗漏的关系 雄鼠的数量。我实验室的进一步研究表明， 甲状腺功能亢进症对女性心肌线粒体的微小影响 老鼠可能是部分有益的。 目标1将比较性别和年龄对以下反应的影响 重复短时间ROS损伤大鼠心肌线粒体 恢复期。实验将使心肌线粒体暴露于 超氧化物生成系统，并评估这种侮辱的后果 线粒体ADS、呼吸作用、能量产量和蛋白质/脂肪 氧化。 目标2将比较性别和年龄在反应上的反应 从离体灌流的大鼠心脏到短时间内产生的“眩晕” 然后这种侮辱对能量状态、呼吸系统的影响 功能和过氧化指数将在线粒体中进行监测 和胞浆。 目标3将评估慢性、升高的氧化应激的影响 (例如，甲亢)对大鼠心脏线粒体ADS水平的影响，以及 这些线粒体对重复短时间ROS侮辱的反应 之后是恢复期。 获得有关广告状态与 心肌线粒体对ROS介导的损伤的脆弱性应该 为制定更好的战略提供线索 预防/治疗妇女，特别是老年妇女的心肌梗塞。

Post-menopausal women have a poorer prognosis after myocardial infarction (MI) than men. Partial explanations for the greater mortality and morbidity in women are loss of beneficial effects of estrogen or gender differences in age, coincident diseases, or treatments. Minimal attention has been given to the plausible alternative explanation that gender influences the basic pathophysiological outcomes of MI, specifically outcomes affected by the cardiac antioxidant defense systems (ADS). ADS provides vital protection against the reactive oxygen species (ROS) that are released during the detrimental ischemia and reperfusion (I/R) events of MI. Mitochondria are a dominant target site of ROS leaked in small amount during normal oxidative phosphorylation and in massive amounts during I/R. Mitochondrial ADS has been reported decreased in the hearts of male rodents by aging. My preliminary research indicates that aging has little effect on cardiac mitochondrial ADS of female rats, and thus provides strong evidence of gender differences in responses of cardiac ADS to aging. Proposed research will test the hypothesis that gender, age and disease are interdependent variables in the vulnerability of cardiac mitochondria to injury by ROS. Hyperthyroidism is the disease for study since it is reported to increase oxidative stress from ROS leakage in association with modified ADS status in cardiac mitochondria of male rats. Further research in my laboratory has indicated that the minimal effects of hyperthyroidism on cardiac mitochondria of female rats may be partially beneficial. AIM 1 will compare the effects of gender and aging On the responses of rat cardiac mitochondria to repeated short ROS insults followed by recovery periods. Experiments will expose cardiac mitochondria to a superoxide generating system and assess consequences of this insult on mitochondrial ADS, respiration, energy yield, and protein/lipid oxidation. AIM 2 will compare the responses of gender and aging on the responses of isolated perfused rat hearts to "stunning" produced by short periods of I/R. Then consequences of this insult on energy status, respiratory function, and indices of peroxidation will be monitored in mitochondria and cytosol. AIM 3 will evaluate the effect of chronic, elevated oxidative stress (e.g., hyperthyroidism) on rat mitochondrial ADS levels in heart, and on the responses of these mitochondria to repeated short ROS insults followed by recovery periods. Information obtained about correlations between ADS status and the vulnerability of cardiac mitochondria to ROS-mediated insults should provide clues to rationale development of better strategies for prevention/treatment of MI in women, especially aged women.