雌激素缺乏状态下补钙对动脉粥样硬化斑块形成的影响及机制研究

It has recently been recognized that calcium supplementation is associated with an increased incidence of myocardial infarction and cardiovascular disease (CVD) in post-menopausal women, which has absorbed great attention from public health area. However, limited study has addressed the reason and potential mechanisms of the detrimental effects of calcium supplementation on the heart. Our previous cross sectional survey revealed that calcium supplementation significantly increased the risk of myocardial infarction in post-menopausal women. Besides, data from our previous randomized controlled trial showed that calcium supplementation coupled with estrogen deficiency significantly increased carotid intima-media thickness. Myocardial infarction is most clinically occurred as a result of the erosion or rupture of atherosclerotic plaque. Additionally, increased carotid intima-media thickness has been well-regarded as a risk factor of atherosclerosis. We, therefore, proposed that calcium supplementation increases the risk of CVD by accelerating atherosclerotic plaque formation in estrogen deficiency. Given its wide and frequent use of calcium supplements, any adverse effects derived from calcium supplementation have important clinical and public health implications. This study was designed to investigate the effects and potential mechanisms of calcium supplementation on the pathological process of atherosclerosis in estrogen deficiency, which was induced by ovariectomy to mimic estrogen deficiency in post-menopausal women. Moreover, this study also aimed at identifying the protective role of estrogen by which preventing against the adverse effects of calcium, and clarifying the safe dose and type of calcium replenisher. This project will provide scientific evidence for directing calcium supplementation and lowering CVD risk in post-menopausal women, and also provide new targets for the clinical and diet prevention and cure of AS in post-menopausal women.

近年研究发现绝经女性补钙显著增加心肌梗死等心血管疾病（CVD）的发病风险，并引起公共卫生领域的极大关注，然而其诱发原因及分子机制尚不明确。我们在人群研究中发现补钙可显著增加绝经女性颈动脉中膜厚度以及心肌梗死的发病风险。动脉粥样硬化（AS）斑块的破裂及脱落是导致心肌梗死的主要原因，而颈动脉中膜厚度的增加又是AS发生的指示性标志，因此，我们推测雌激素缺乏状态下补钙可能通过促进AS斑块的形成，进而增加CVD发生的风险。考虑到绝经女性补钙的广泛性和高频性，其可能导致的任何风险都关系着我国公共健康，应被重视并有必要进行深入研究。本项目拟通过卵巢去除术模拟女性绝经状态，阐述雌激素缺乏状态下补钙与AS斑块形成的关系及其作用机制，明确雌激素如何发挥保护作用，并对安全的补钙剂量以及钙剂种类进行深入研究，为指导绝经女性科学补钙、降低补钙引起的CVD风险提供科学依据，为膳食干预或临床防治绝经女性AS提供新靶点。

补钙被认为是防治骨质疏松的良好手段并被广泛推荐。然而，近来针对绝经期女性补钙研究的关注程度进一步提高。有研究报道显示，补钙可能增加绝经期女性心血管疾病的发生风险。然而，绝经期女性补钙诱发心血管疾病的发病率升高的分子机制尚不明确。本研究将探讨补钙对雌激素缺乏状态下动脉粥样硬化形成的影响并深入揭示其分子机制。研究采用卵巢去除的ApoE-/-、C57BL/6小鼠及血管内皮细胞、平滑肌细胞及巨噬细胞为体外研究对象，采用卵巢去除术及无雌激素培养基模拟雌激素缺乏状态并进行补钙干预。研究结果表明，雌激素缺乏状态下补钙显著促进ApoE-/-小鼠动脉粥样硬化斑块的形成。机制研究表明，雌激素缺乏状态下补钙通过上调TRPC1的表达增加细胞外钙内流，进而激活ERK1/2/NFκB信号传导通路，最终导致VCAM-1水平的升高、单核细胞粘附以及动脉粥样硬化板块形成。雌激素补充可显著抑制补钙引起的动脉粥样硬化斑块形成。补钙引起的动脉粥样硬化斑块形成风险增加与补钙剂量密切相关，当补钙剂量达正常钙剂量的2.5倍以上时可显著增加该风险。此外，与无机钙剂（碳酸钙）相比较，有机钙剂（柠檬酸钙）的补充未表现出显著的降低斑块增加的作用。上述研究结果提示雌激素缺乏状态下的过量钙补充具有增加动脉粥样硬化发生风险的可能性，过量钙摄入增加的动脉粥样硬化发生风险与雌激素缺乏关系密切，补钙的剂量而非钙剂的种类是决定该风险发生的关键因素。雌激素缺乏状态下，女性补钙应在考虑膳食钙摄入量的基础上合理选择钙补充剂的剂量，以防止危害心血管疾病等不良事件的产生。