MITOCHONDRIAL FUNCTION--AGE, GENDER, AND DISEASE EFFECTS

线粒体功能——年龄、性别和疾病的影响

• 批准号: 2411404
• 负责人: MARY F KANZ
• 金额: $ 7.35万
• 依托单位: UNIVERSITY OF TEXAS MED BR GALVESTON
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-07-15 至 1999-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2411404
• 关键词: age difference; aging; gender difference; hyperthyroidism; mitochondria; myocardial infarction; myocardium; oxidative stress; pathologic process

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.

绝经后女性心肌梗死后预后较差 梗塞（MI）的发生率高于男性。对更大的部分的解释 妇女的死亡率和发病率是由于失去了 雌激素或年龄、同时患有疾病的性别差异，或 治疗。对看似合理的情况给予了最低限度的关注 另一种解释是性别影响基本的 MI 的病理生理结果，特别是受以下因素影响的结果 心脏抗氧化防御系统（ADS）。 ADS 提供了至关重要的 防止释放的活性氧 (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和大量的过程中 I/R。 据报道，男性心脏中的线粒体 ADS 减少 啮齿类动物因衰老而死亡。我的初步研究表明，衰老已经 对雌性大鼠心脏线粒体ADS影响不大，因此 提供了心脏反应中性别差异的有力证据 ADS 导致老化。拟议的研究将检验以下假设：性别、 年龄和疾病是影响脆弱性的相互依存的变量 ROS 损伤心脏线粒体。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 渗漏与心脏线粒体 ADS 状态改变相关 雄性大鼠。我的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极小 老鼠可能是部分有益的。 AIM 1 将比较性别和老龄化对以下人员的反应的影响 大鼠心脏线粒体重复短暂的 ROS 损伤，然后 恢复期。 实验将把心肌线粒体暴露于 超氧化物生成系统并评估这种侮辱的后果 线粒体 ADS、呼吸、能量产量和蛋白质/脂质 氧化。 AIM 2 将比较性别和年龄对反应的反应 短期内产生的离体灌注大鼠心脏“令人震惊” I/R 的。然后这种侮辱对能量状态、呼吸系统的影响 将监测线粒体的功能和过氧化指数 和细胞质。 AIM 3 将评估慢性氧化应激升高的影响 （例如，甲状腺功能亢进症）对大鼠心脏线粒体 ADS 水平的影响，以及 关于这些线粒体对重复短暂的 ROS 损伤的反应 接下来是恢复期。 获得有关 ADS 状态和 心脏线粒体对 ROS 介导的损伤的脆弱性应该 为合理制定更好的战略提供线索 预防/治疗女性尤其是老年女性的心肌梗死。