雌激素调控脂联素在HRT心血管副作用中分子机理研究

Postmenopausal estrogen withdrawal is the key factor that leads to high incidence of cardiovascular disease in women. However, the protection effect of hormone replacement therapy (HRT) on cardiovascular is age related. Because estrogen itself has no direct adverse effects on the cardiovascular system, HRT associated cardiovascular side effects may be caused by the indirect influence of estrogen on other tissues. Recent studies have found that the feature of fat tissues is totally different in different ages, so estrogen may have opposite effect on fat tissues of different ages. Although visceral fat accumulation is reduced with HRT, secretion of cardiovascular protection factor – adiponectin is decreased significantly. We found that the expression of miR-935 was higher in visceral fat of postmenopausal women, and adiponectin might be the target gene of miR-935. Moreover, the promoter region of miR-935 had estrogen response element and miR-935 could be regulated by estrogen. In this proposal, we innovatively studied that miRNA regulated by estrogen and influenced secretion of adiponectin in order to find out the mechanisms of increasing HRT associated cardiovascular side effects in postmenopausal aged women. Also it might provide new means for the prevention and treatment of HRT associated cardiovascular side effects.

绝经后雌激素水平下降是导致女性心血管疾病高发的关键因素，但雌激素替代治疗（HRT）对心血管的保护作用存在年龄差异。由于雌激素本身对心血管系统无直接损害作用，HRT对心血管的不利作用可能是雌激素通过影响其它组织产生的间接作用所致。近来研究发现，不同年龄脂肪功能特征完全不同，雌激素对不同年龄的脂肪组织可能产生相反的作用。HRT尽管减少了绝经后女性内脏脂肪蓄积，却同时导致心血管保护因子adiponectin的分泌明显减少。我们通过绝经前后女性内脏脂肪的miRNA芯片发现miR-935在绝经后女性内脏脂肪表达明显升高，而adiponectin是其可能的靶基因；并且发现miR-935的启动子区域具有雌激素反应元件，可受雌激素调控。本课题创新性的从雌激素调控miRNA影响脂肪因子adiponectin的分泌入手，搞清HRT导致绝经后老年女性心血管事件增加的分子机理，为防治HRT心血管副作用提供新手段。

绝经后雌激素水平下降是导致女性心血管疾病高发的关键因素，但雌激素替代治疗（HRT）对心血管的保护作用存在年龄差异。由于雌激素本身对心血管系统无直接损害作用，HRT对心血管的不利作用可能是雌激素通过影响其它组织产生的间接作用所致。研究发现，不同年龄脂肪功能特征完全不同，雌激素对不同年龄的脂肪组织可能产生相反的作用。HRT尽管减少了绝经后女性内脏脂肪蓄积，却同时导致心血管保护因子adiponectin的分泌明显减少。我们通过绝经前后女性内脏脂肪的长非编码RNA（long non-coding RNA，lncRNA）芯片分析发现Gas5在绝经后女性内脏脂肪表达明显升高，导致脂肪因子adiponectin表达下降，而visfatin和resistin表达增加；炎症因子TNFα、MCP-1、IL-6表达也增加。进一步研究发现和胰岛素代谢通路密切相关的IGF2BP是Gas5的下游基因。本课题创新性的从雌激素调控lncRNA影响脂肪功能入手，阐明HRT导致绝经后老年女性心血管事件增加的分子机理，为防治HRT心血管副作用提供新手段。