Gender Differences in Caloric Restriction Cardioprotection

描述（由申请人提供）：已证明心血管疾病患病率存在显著的性别差异。绝经前女性患心血管疾病的风险大大低于同龄男性，而绝经后，女性心血管疾病的发病率急剧上升。女性心脏保护的这种年龄依赖性逆转归因于绝经后女性中循环女性性激素（例如雌激素）的损失。动物模型的研究也为雌激素的直接心脏保护作用提供了很好的证据。然而，包括NIH妇女健康倡议试验在内的临床试验未能证明绝经后妇女中激素替代疗法（HRT）的心脏保护益处。解决目前的差异需要更全面地了解心脏保护中性别差异所涉及的细胞和分子机制。CR是研究最广泛的干预措施，可以延长寿命并防止压力。我们的初步研究表明，在CR下，女性比男性对慢性儿茶酚胺应激的耐受性差。如果我们的研究结果，CR是没有保护绝经前女性的这项研究得到证实，那么了解介导的女性不良反应的分子机制可能会揭示这些机制介导的HRT治疗绝经后妇女的不良后果。有两个主要假设：假设A：热量限制保护雄性小鼠的心脏免受慢性儿茶酚胺应激，但在雌性小鼠中没有观察到。假设B：热量限制在男性和女性的基因调控中诱导了许多差异，并且确定那些介导雌性热量限制小鼠中儿茶酚胺应激的不良影响的基因可以提供对在绝经前雌激素水平存在下具有保护作用的机制的深入了解。我们的研究将揭示新的机制，性别差异的心脏保护热量限制。对公共卫生的影响是明确的：了解热量限制的男性而不是女性的心脏保护机制，为绝经后妇女心血管疾病的治疗提供了方向。公共卫生相关性：绝经前妇女患心血管疾病的风险降低，但绝经后心血管疾病的发病率急剧上升。循环中女性性激素（例如雌激素）的丧失被认为是导致这种年龄依赖性逆转的原因。然而，包括NIH妇女健康倡议试验在内的临床试验表明，激素替代疗法（HRT）在减少CVD结果方面无效，实际上可能会增加CVD结果。目前的应用是调查在热量限制中心脏保护的性别差异。我们已经发现，延长寿命和保护免受压力的热量限制干预只保护雄性小鼠的心脏免受心脏压力，但这在雌性小鼠中没有观察到。了解这些不良反应的分子机制可能有助于揭示绝经后妇女HRT治疗不良后果的机制，并为绝经后妇女CVD的治疗提供指导。

DESCRIPTION (provided by applicant): Significant gender differences in the prevalence of cardiovascular disease have been demonstrated. The risk of developing cardiovascular disease is considerably lower in pre-menopausal females than in age-matched males, whereas after menopause, the rate of cardiovascular disease in females rises sharply. This age- dependent reversal of female cardioprotection has been attributed to the loss of circulating female sex hormones, e.g. estrogen, in post-menopausal women. Studies in animal models also provide good evidence for direct cardioprotection by estrogen. However, clinical trials including the NIH Women's Health Initiative trial have failed to demonstrate cardioprotective benefit from hormone replacement therapy (HRT) in post- menopausal women. Resolving the current disparity requires a more complete understanding of cellular and molecular mechanisms involved in gender differences in cardioprotection. CR is the most extensively studied intervention that extends longevity and protects against stress. Our preliminary studies demonstrate that under CR, females are less tolerant to chronic catecholamine stress than males. If our findings that CR is not protective in pre-menopausal females are confirmed by this study, then understanding the molecular mechanisms mediating the adverse effects in females may shed light on those mechanisms mediating the adverse outcome of HRT therapy in post-menopausal women. There are two major hypotheses: Hypothesis A: Caloric restriction protects the heart of male mice from chronic catecholamine stress, but this is not observed in female mice. Hypothesis B: Caloric restriction induces numerous differences in gene regulation in males and females, and determining those genes that mediate the adverse effects of catecholamine stress in female caloric restricted mice may provide insight into mechanisms that are protective in the presence of pre-menopausal estrogen levels. Our study will reveal novel mechanisms of gender differences in cardioprotection in caloric restriction. The implications for Public Health are clear: understanding the cardiac protective mechanisms in caloric restricted males but not in females provide the direction for the treatment of cardiovascular disease in post-menopausal women. PUBLIC HEALTH RELEVANCE: Pre-menopausal women have reduced risk for CVD, but the rate of CVD rises sharply after menopause. The loss of circulating female sex hormones, e.g. estrogen, has been suggested to contribute to this age- dependent reversal. However, clinical trials including the NIH Women's Health Initiative trial suggest that hormone replacement therapy (HRT) is ineffective in reducing, and may actually increase CVD outcomes. The current application is to investigate the gender differences in cardioprotection in caloric restriction. We have found that the intervention of caloric restriction that extends longevity and protects against stress only protects the heart of male mice from cardiac stress, but this is not observed in female mice. Understanding the molecular mechanisms mediating the adverse effects in females may shed light on those mechanisms mediating the adverse outcome of HRT therapy in post-menopausal women and provide the direction for the treatment of CVD in post-menopausal women.