Mechanisms of Exercise & Estrogen Induced Cytoprotection

描述(由申请人提供)： 虽然最近的临床试验促使对雌激素治疗进行了重要的重新评估，但大多数证据表明，绝经后心脏病死亡风险的增加可能会被雌激素缓解，导致心脏病发病率下降40%-50%。尽管如此，考虑到一些女性服用雌激素可能会加速疾病进展，研究预防绝经后心脏病死亡率增加的替代干预措施是非常有意义的。降低缺血性心脏病死亡率的一个潜在的替代疗法是耐力运动。众所周知，运动可以提高对心肌缺血和再灌流的耐受性。耐力运动可改善收缩性能，缩小梗塞面积。运动对心脏保护作用的解释机制(S)仍然不清楚。雌激素和运动似乎具有相似的心脏保护作用，而且雌激素被证明是通过保护心肌细胞和血管内皮细胞来实现的。这项拟议的研究将通过以下几个方面加深我们对运动和雌激素诱导的心脏保护机制的理解：(1)运动的保护作用是否针对心肌细胞和血管内皮细胞，(2)运动是否保护心肌细胞和内皮细胞免于凋亡而不是坏死细胞死亡，(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的心脏保护相似，以及运动诱导的保护是否性别相关)，以及(4)运动和雌激素是否通过NFkB介导的信号促进心脏保护。这些目标将使用从运动大鼠分离的心肌细胞和主动脉内皮细胞，使用特定的药物抑制剂来实现。这些研究将提高我们对运动诱导的细胞保护机制的理解，可能会导致降低心脏病死亡率的替代疗法。

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.