巨噬细胞的维生素D受体激活改善血管钙化的机制研究

Vascular calcification is a common finding in patients suffered with hypertension, and diabetes, which mainly occurs in the media of arteries. Accumulation of macrophages, which is associated with vascular calcification, promotes VSMC calcification by secreting inflammatory cytokines. Growing evidences have demonstrated that Vitamin D treatment contributes to cardiovascular survival benefits, but the mechanism of inhibitory role of Vitamin D in the development of vascular calcification remains obscure. Recently, we found that the expression of interleukin-1β (IL-1β) and interleukin-6 (IL-6) were also increased with hypertension and vascular calcification. We further demonstrated that serum levels of vitamin D were inversely correlated with inflammatory cytokines (IL-6, IL-1β) in peripheral blood which positively correlated coronary artery calcification score in the general population. Therefore, we hypothesized that relieving vascular smooth muscle cell (VSMC) differentiation into osteoblastic-like cells are associated with reduced inflammatory cytokine expression induced by vitamin D receptor activators(VDRAs) on macrophages, which leads to the vascular anticalcification. The present study aims to determine mechanism of vitamin D receptor activators (VDRAs) on macrophages regulate inflammatory cytokine expression participating in function of VSMC differentiation contributing to mediate vascular calcification and the mechanism of VDRAs inhibiting vascular calcification in the animal model. This study provides the support of VDRAs may contribute to their observed cardiovascular survival benefits and a new potential therapeutic target for early treatment of vascular calcification.

血管钙化是高血压、糖尿病等常见疾病普遍存在的病理表现，主要发生在血管中膜，最新研究证实中膜钙化同时存在巨噬细胞的大量浸润，其分泌的炎症因子可促进平滑肌细胞钙化。大量临床资料已经证明维生素D在预防心血管疾病过程中发挥着重要的作用，但如何抑制血管钙化的机制仍不清楚。我们前期研究发现高血压钙化者炎症因子表达明显增加，进一步发现维生素D水平缺乏者外周血的炎症因子(IL-6，IL-1β)明显增高，后者与冠脉钙化积分正相关。于是，我们假设在血管钙化过程中，巨噬细胞上维生素D受体激活(VDRAs)可以抑制血管炎症反应，减缓平滑肌细胞向成骨样细胞转分化，从而减少血管中膜钙化的发生。本项目将研究 1）VDRAs调控巨噬细胞炎症因子的分泌参与平滑肌细胞分化功能的机制 2）在血管钙化模型中，VDRAs改善血管钙化的机制。该研究将为维生素D心血管保护作用提供理论依据，并为防治血管钙化新药开发提供了潜在的干预靶点。

血管钙化/硬化是高血压、糖尿病等常见疾病普遍存在的病理表现。主要发生在血管中膜，最新研究证实中膜钙化同时存在巨噬细胞的大量浸润，其分泌的炎症因子可促进平滑肌细胞钙化。大量临床资料已经证明维生素D在预防心血管疾病过程中发挥着重要的作用，但如何抑制血管钙化的机制仍不清楚。目前研究内容主要包括三部分： VDRAs 调控巨噬细胞炎症因子的分泌参与平滑肌细胞分化功能的机制；研究在血管钙化模型中，VDRAs改善血管钙化的机制；高血压血管硬化患者炎症因子(IL-6，IL-1β)的表达变化。进一步研究维生素D 水平缺乏患者与外周血炎症因子(IL-6，IL-1β)及血管硬化程度的变化。结果发现：1）VDR siRNA在巨噬细胞中是有作用的，knock down效率差不多70-80%。检测几个VDR下游基因CYP24A1, CYP3A4 ，CYP3A5和TRPV6的表达水平变化发现一致性好，证明VDR siRNA在巨噬细胞中是有作用的。2）说明帕立骨化醇治疗组有降低血压、减慢心率的趋势，似乎优于骨化醇治疗组，我们研究团队进一步加大样本量，来验证这个结论。3）帕立骨化醇治疗组明显降低左右侧颈总动脉内中膜厚度，而骨化醇治疗组降低右侧颈总动脉内中膜厚度，并且在降低颈总动脉内中膜厚度上，帕立骨化醇治疗组优于骨化醇治疗组。4）血管硬化或钙化可作为亚临床靶器官损害中间标志物预测心脑血管事件，而且对骨质疏松有一定预测价值，维生素D缺乏和不足的患者，其维生素D的水平越低，血管硬化程度增加，尤其是反应外周血管疾病的踝臂指数明显下降。.因此关注并加强对血管钙化的共同发病机制的研究，为维生素D心血管保护作用提供理论依据，并为防治血管钙化新药开发提供了潜在的干预靶点；对于阐明血管钙化的发病和临床防治血管钙化，最终预防心血管事件的发生具有重要的意义。