VITAMIN D AND IMMUNOMODULATION IN CORONARY ARTERY DISEASE

描述(申请人提供)：冠状动脉疾病增加的患病率非常高，世界上近50%的老年人口缺乏维生素D。低水平的维生素D会增加心脏病、中风、高血压和糖尿病的风险。球囊血管成形术/支架植入后血管造影再狭窄的发生率与维生素D缺乏/不足的发生率密切相关。目前还没有数据可以预测哪些患者会在冠状动脉介入治疗后发生内膜增生和支架内再狭窄。本研究的目的是评估维生素D状态对控制良好的猪动脉粥样硬化模型干预后冠状动脉再通的结果指标的影响，并确定潜在的细胞和分子机制。中心假设是冠状动脉介入治疗后的内膜增生取决于维生素D的状态，补充维生素D可以抑制炎症。我们建议使用一种高脂血症和动脉粥样硬化的小型猪模型，饲喂维生素D缺乏、维生素D充足和维生素D补充的日粮。动物将接受球囊血管成形术或血管内支架置入术。Aim 1中的假设预测，维生素D缺乏会通过增加血管平滑肌细胞增殖(SMC)和增强炎症来增加冠状动脉介入治疗后的内膜增生和再狭窄。AIM 2中的假设预测，补充维生素D将通过减少SMC的增殖和抑制炎症来减少冠状动脉介入治疗后的内膜增生和再狭窄。Aim 3的假设预测，维生素D通过抑制炎症和通过抑制Importin-β3的转录和翻译而减少核因子-kB转位到细胞核，从而减少内膜增生和再狭窄。通过左心室造影和光学相干断层扫描对冠状动脉介入治疗后缺乏、充足和补充维生素D的高胆固醇血症和动脉粥样硬化小型猪进行为期六个月的跟踪观察，以评估心功能并量化节段内最小管腔直径、直径狭窄、晚期丢失和内膜增生。此外，血清25-羟基维生素D水平、炎症介质和细胞因子、血脂谱和其他生化和临床变量。将进行冠状动脉的组织学和免疫组织化学评估，包括内膜厚度、内膜增生、管腔面积、内膜-中层比率、斑块发展和斑块溃疡、再闭塞和炎性细胞渗透。此外，还将检测VDR、CYP24A1、CYP27B1、NF-kB、Importin-β3和Prohibitin在分离的平滑肌细胞中的mRNA和蛋白表达。这些研究将为我们的假设提供概念性支持，并使我们能够评估补充维生素D在预防冠心病患者冠状动脉介入治疗后临床并发症方面的有效性。

DESCRIPTION (provided by applicant): Increased prevalence of coronary artery disease is very high and almost 50% of elderly population of the world is vitamin D-deficient. Low levels of vitamin D have increased risks of heart disease, stroke, hypertension, and diabetes. The incidence of angiographic restenoses following balloon angioplasty/stent implantation correlates well with the incidence of vitamin D deficiency/insufficiency. There is no data to predict which patient will develop intimal hyperplasia and in-stent restenosis following coronary intervention. The purpose of this study is to evaluate the effect of vitamin D status on the outcome measures of coronary patency following intervention in a well-controlled swine model of atherosclerosis and to determine the underlying cellular and molecular mechanisms. The central hypothesis is that intimal hyperplasia after coronary intervention depends on vitamin D status and supplementation with vitamin D inhibits inflammation. We propose to utilize a hyperlipidemic and atherosclerotic microswine model fed with vitamin D-deficient, vitamin D-sufficient, and vitamin D-supplemented diet. Animals will undergo balloon angioplasty or intravascular stenting. The hypothesis in Aim 1 predicts that vitamin D deficiency will increase intimal hyperplasia and restenosis following coronary artery intervention by increasing smooth muscle cell proliferation (SMC) and enhancing inflammation. The hypothesis in Aim 2 predicts that vitamin D supplementation will decrease intimal hyperplasia and restenosis following coronary artery intervention by decreasing SMC proliferation and inhibiting inflammation. The hypothesis of Aim 3 predicts that vitamin D decreases intimal hyperplasia and restenosis by inhibiting inflammation and decreasing smooth muscle cell proliferation by decreasing translocation of NF-kB to the nucleus via inhibition of transcription and translation of importin-¿3. Hypercholesterolemic and atherosclerotic microswine with vitamin D deficiency, sufficiency and supplementation will be followed over a period of six months following coronary intervention with left ventriculogram and optical coherence tomography to assess cardiac function and quantify in-segment minimal luminal diameter, diameter stenosis, late loss and intimal hyperplasia. Also, serum levels of 25-hydroxyvitamin D, inflammatory mediators and cytokines, lipid profile and other biochemical and clinical variables. Histological and immunohistochemical evaluation of coronary arteries for intimal thickness, intimal hyperplasia, lumen area, intima-media ratio, plaque development and plaque ulceration, and re-occlusion, and infiltration of inflammatory cells will be performed. Also the mRNA and protein expression of VDR, CYP24A1, CYP27B1, NF-kB, importin-¿3, and prohibitin in isolated smooth muscle cells will be examined. These studies will provide the conceptual support of our hypothesis and position us to assess the effectiveness of vitamin D supplementation in the prevention of clinical complications following coronary interventions in patients with coronary artery disease.