Gender Differences in Caloric Restriction Cardioprotection

说明(由申请人提供)：心血管疾病患病率存在显著的性别差异。绝经前的女性患心血管疾病的风险比年龄匹配的男性低得多，而绝经后女性患心血管疾病的比例急剧上升。这种与年龄相关的女性心脏保护的逆转归因于绝经后女性循环中的女性性激素的丧失，例如雌激素。动物模型的研究也为雌激素直接保护心脏提供了很好的证据。然而，包括NIH妇女健康倡议试验在内的临床试验未能证明激素替代疗法(HRT)对绝经后妇女的心脏保护作用。解决目前的差异需要对心脏保护中性别差异所涉及的细胞和分子机制有更全面的了解。CR是研究最广泛的延年益寿和抵抗压力的干预措施。我们的初步研究表明，在CR条件下，女性对慢性儿茶酚胺应激的耐受性低于男性。如果我们的研究结果证实了CR对绝经前女性没有保护作用，那么了解女性不良反应的分子机制可能有助于了解HRT治疗绝经后女性不良结局的机制。有两个主要的假设：假设A：卡路里限制保护雄性小鼠的心脏免受慢性儿茶酚胺应激的影响，但这在雌性小鼠身上没有观察到。假设B：卡路里限制导致雄性和女性在基因调控上的许多差异，确定那些介导儿茶酚胺应激对雌性卡路里限制小鼠不利影响的基因可能有助于深入了解绝经前雌激素水平存在时具有保护作用的机制。我们的研究将揭示热量限制中心脏保护的性别差异的新机制。对公共卫生的影响是明确的：了解热量限制男性而不是女性的心脏保护机制为绝经后女性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。循环中的女性性激素的丢失，如雌激素，被认为是这种年龄相关性逆转的原因。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)在减少心血管疾病方面无效，实际上可能会增加心血管疾病的结局。目前的应用是调查热量限制在心脏保护方面的性别差异。我们已经发现，延长寿命和防止压力的卡路里限制干预只保护雄性小鼠的心脏免受心脏应激的影响，但这在雌性小鼠身上没有观察到。了解女性HRT不良反应的分子机制，有助于了解HRT治疗绝经后妇女不良结局的分子机制，为绝经后妇女心血管疾病的治疗提供指导。

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.