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）的发病率高于男性。部分原因是 妇女的死亡率和发病率是妇女丧失了 雌激素或年龄性别差异，并发疾病，或 治疗。很少有人注意到 另一种解释是，性别影响着 MI的病理生理结局，特别是受以下因素影响的结局 心脏抗氧化防御系统（ADS）ADS提供重要的 保护免受释放的活性氧（ROS） 在MI的有害缺血和再灌注（I/R）事件期间。 线粒体是少量ROS泄漏的主要靶点 在正常的氧化磷酸化过程中， I/R。 据报道，男性心脏中的线粒体ADS减少， 啮齿动物的衰老。我的初步研究表明， 对雌性大鼠的心脏线粒体ADS几乎没有影响，因此 提供了强有力的证据，表明心脏反应存在性别差异， 向衰老致敬。拟议中的研究将检验性别， 年龄和疾病是脆弱性的相互依赖的变量， 心肌线粒体损伤的ROS。甲状腺机能亢进症是一种 因为据报道它会增加ROS的氧化应激， 心肌线粒体中与改良ADS状态相关的渗漏 雄性老鼠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影响 老鼠可能部分有益。 AIM 1将比较性别和年龄对 大鼠心肌线粒体反复短暂的ROS损伤， 恢复期。 实验将使心脏线粒体暴露于 超氧化物生成系统，并评估这种损伤对 线粒体ADS、呼吸、能量产量和蛋白质/脂质 氧化 目的2将比较性别和年龄对反应的反应 离体灌流的大鼠心脏的“休克”产生的短时间 I/R。那么这种侮辱对能量状态，呼吸系统 功能，并将在线粒体中监测过氧化指标 和胞质溶胶。 目的3将评估慢性氧化应激的影响， (e.g.,甲状腺功能亢进）对大鼠心脏线粒体ADS水平的影响，以及 这些线粒体对反复短时间ROS损伤的反应 然后是恢复期。 获得的关于ADS状态与 心肌线粒体对ROS介导的损伤的脆弱性应该 为更好的战略的合理制定提供线索， 预防/治疗女性MI，尤其是老年女性。

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.