雌激素缺乏情况下补钙对血管内皮细胞损伤的影响及其机制研究

Cardiovascular disease (CVD) is the first killer for human life at present.Calcium supplementation is an effective measurement to prevent osteoporosis for postmenopausal women.Recently, population-based study has showed that in postmenopausal women,calcium supplementation may increase the risk of CVD.Cross-sectional study of our group have found that calcium supplementation will increase the incidence of myocardial infarction in postmenopausal women.In vitro we have also found that calium supplementation can increase the expression of inflammatory factor in the condition of estrogen deficiency.The endothelial functional integrity is very important for the preventation of atherosclerosis and cardiovascular disease.However, the definitely molecular mechanism of the effect of calcium supplmentation on endothelial function is unclear now.Calcium supplementation has became a prevailing habit for postmenopausal women and the group of calcium supplementation is huge.calcium supplementation is a hot spots because it concerns our country publilc health,any risk it will made should be paid attention to and that a in-depth study is demand .Therefore,this project will adopt the crowd randomized double-blind trial to detect the effect of calcium supplementation on endothelial function in postmenopausal women,detect the definitely effect and mechanism of calcium supplementation on endothelial function in the condition of estrogen deficiency in vitro and in vivo.This project will provide a guidance for menopausal women who take calcium supplements, and reduce the risk of calcium supplementation.

心血管疾病(CVD)是威胁人类生命的头号杀手。补钙是女性绝经后预防骨质疏松的有效手段。但近年人群研究表明绝经女性补钙显著增加CVD的发病风险。我们课题组前期人群横断面研究发现，补钙能增加女性绝经后心肌梗死的发病率。我们通过体外实验中发现雌激素缺乏协同高钙能增加血管内皮细胞炎性因子表达。血管内皮细胞功能完整性对防止动脉粥样硬化（AS）及CVD的发生具有重要作用。然而，在雌激素缺乏情况下补钙如何导致血管内皮细胞功能损伤的具机制尚不明确。绝经期女性补钙已经成为一种风尚并有很大的补钙群体，这关系我国公共健康，是当今预防医学的研究热点，其可能导致的任何风险应被重视并有必要进行深入研究。因此，本项目拟通过人群随机双盲试验明确补钙对绝经期女性血管内皮的影响，利用体内外和动物实验研究探索雌激素缺乏状态下补钙对内皮细胞功能的影响和其机制。本项目实施将为指导绝经期女性科学补钙及降低补钙可能带来的风险。

我国居民补钙已进行约30年，然而补钙对我国居民健康产生怎样的影响目前尚无明确报道。本研究采用动物实验以及体外细胞实验相结合的技术手段分别对雌激素缺乏状态下补钙对内源性胆固醇的代谢以及血管内皮细胞功能的影响进行研究，并采用分子生物学技术手段及其机制进行深入研究。补钙对雌激素缺乏状态下内源性胆固醇代谢的研究结果：动物实验结果表明，雌激素缺乏状态下补钙显著增加血中总胆固醇及低密度脂蛋白胆固醇水平；在雌激素正常状态下补钙对血中胆固醇水平无显著影响。补钙对雌激素缺乏状态下血管内皮细胞功能的研究结果：与假手术组动物相比，卵巢去除组动物血浆中炎性因子（TNF-alpha、IL-1beta）水平显著升高。补钙显著升高了卵巢去除组小鼠的血浆及血管内皮的VCAM-1的水平，而在假手术组内，补钙对小鼠血浆及血管内皮的VCAM-1的水平无显著影响。研究发现在雌激素缺乏状态下，补钙通过抑制肝脏胆固醇的分解代谢导致血中总胆固醇水平的上升；此外，补钙通过协同炎性因子增加了血管内皮细胞VCAM-1的表达。在正常雌激素水平状态下，补钙对肝脏胆固醇代谢及血管内皮细胞中VCAM-1的表达均无显著影响。因此，雌激素缺乏状态下补钙可能通过增加血中总胆固醇含量及血管内皮粘附因子的表达进而增大AS及CVD的发病风险。