Mechanisms of Exercise & Estrogen Induced Cytoprotection

运动机制

• 批准号: 6862123
• 负责人: Karyn L Hamilton
• 金额: $ 9.73万
• 依托单位: COLORADO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-04-01 至 2010-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6862123
• 关键词: age difference; aorta; apoptosis; biological signal transduction; cardiac myocytes; cardiovascular disorder prevention; cytoprotection; disease /disorder model; estrogens; exercise; gender difference; heart contraction; hormone therapy; laboratory rat; myocardial infarction; myocardial ischemia /hypoxia; nonhuman therapy evaluation; nuclear factor kappa beta; ovariectomy; postmenopause; transcription factor; vascular endothelium

DESCRIPTION (provided by applicant): While recent clinical trials have prompted an important reevaluation of estrogen therapy, the majority of evidence suggests that the post-menopausal heightened risk of mortality from heart disease may be attenuated by estrogen, resulting in a 40-50% decrease in the incidence of heart disease. Nonetheless, given the potential for accelerated disease progression associated with estrogen replacement in some women, investigating alternative interventions for protecting against the post-menopausal increase in mortality from heart disease is of great interest. One potential alternative therapy for decreasing the risk of mortality from ischemic heart disease is endurance exercise. It is well established that exercise improves tolerance to myocardial ischemia and reperfusion. Endurance exercise improves contractile performance and attenuates infarction size. The mechanism(s) to explain the cardioprotective effect of exercise remain elusive. Estrogen and exercise appear to exert similar cardioprotective effects and estrogen has been shown to do so via protection of both cardiac myocytes and vascular endothelial cells. The proposed research will further our understanding of mechanisms of exercise and estrogen-induced cardioprotection by addressing: (1) whether the protective effects of exercise are targeted at cardiomyocytes versus vascular endothelium, (2) if exercise protects cardiomyocytes and endothelial cells against apoptotic versus necrotic cell death, (3) whether exercise-mediated protection is dependent on estrogen (i.e., whether exercise protects similarly pre- and post-menopause and whether exercise-induced protection is gender-dependent), and (4) if exercise and estrogen facilitate cardioprotection via NFkB-mediated signaling. These aims will be addressed using cardiac myocytes and aortic endothelial cells isolated from exercised rats, employing specific pharmacological inhibitors. These studies will improve our understanding of the mechanisms of exercise-induced cytoprotection, perhaps leading to alternative therapies for decreasing mortality from heart disease.

描述（由申请人提供）： 虽然最近的临床试验促使人们对雌激素治疗进行重要的重新评估，但大多数证据表明，雌激素可能会降低绝经后心脏病死亡率升高的风险，从而使心脏病发病率降低 40-50% 。 尽管如此，考虑到一些女性与雌激素替代相关的疾病加速进展的可能性，研究防止绝经后心脏病死亡率增加的替代干预措施非常有意义。 降低缺血性心脏病死亡风险的一种潜在替代疗法是耐力运动。 众所周知，运动可以改善心肌缺血和再灌注的耐受性。 耐力运动可以改善收缩性能并减少梗塞面积。 解释运动的心脏保护作用的机制仍然难以捉摸。 雌激素和运动似乎具有相似的心脏保护作用，雌激素已被证明是通过保护心肌细胞和血管内皮细胞来实现这一作用的。 拟议的研究将通过解决以下问题进一步了解运动和雌激素诱导的心脏保护机制：（1）运动的保护作用是否针对心肌细胞与血管内皮，（2）运动是否可以保护心肌细胞和内皮细胞免受凋亡与坏死的影响细胞死亡，（3）运动介导的保护是否依赖于雌激素（即运动是否对绝经前和绝经后具有类似的保护作用，以及运动引起的保护是否性别依赖性），以及（4）运动和雌激素是否通过 NFkB 介导的信号传导促进心脏保护。 这些目标将通过使用从运动大鼠中分离的心肌细胞和主动脉内皮细胞并采用特定的药理学抑制剂来实现。 这些研究将增进我们对运动诱导的细胞保护机制的理解，或许会带来降低心脏病死亡率的替代疗法。