VITAMIN D AND IMMUNOMODULATION IN CORONARY ARTERY DISEASE

冠状动脉疾病中的维生素 D 和免疫调节

• 批准号: 8703297
• 负责人: Devendra K. Agrawal
• 金额: $ 7万
• 依托单位: CREIGHTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-07-16 至 2017-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8703297
• 关键词: 25-hydroxyvitamin D; Address; Angiography; Angioplasty; Animals; Area; Atherosclerosis; Balloon Angioplasty; Biochemical; Biological Assay; Blood Vessels; Caliber; Cardiac; Cardiology; Cardiovascular system; Cell Nucleus; Cell Proliferation; Cells; Cellular biology; Cholesterol; Clinical; Clinical Research; Controlled Study; Coronary; Coronary Arteriosclerosis; Coronary artery; Data; Development; Diabetes Mellitus; Diet; Effectiveness; Elderly; Evaluation; Exposure to; Extracellular Matrix; Family suidae; General Population; Genetic Transcription; Goals; Growth; Heart; Heart Diseases; Housing; Human; Hyperplasia; Hypertension; Immune response; Immunohistochemistry; Importins; Incidence; Infiltration; Inflammation; Inflammation Mediators; Inflammatory; Injury; Interferons; Interleukin-6; Intervention; Investigation; Left; Lesion; Lighting; Lipids; Metals; Modeling; Molecular; Molecular Biology; NF-kappa B; Optical Coherence Tomography; Outcome; Outcome Measure; Pathology; Patients; Population; Positioning Attribute; Prevalence; Prevention; Procedures; Research; Role; Seasons; Serum; Site; Smooth Muscle Myocytes; Stenosis; Stents; Stroke; Sunlight; Supplementation; TNF gene; Testing; Thick; Thrombosis; Tissues; Translating; Translations; Ulcer; Variant; Vascular Diseases; Vitamin D; Vitamin D Deficiency; Wit; animal facility; coronary angioplasty; cytokine; dietary supplements; feeding; heart disease risk; immunoregulation; implantation; intima media; mRNA Expression; prevent; prohibitin; protein expression; response to injury; restenosis; treatment strategy

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.

描述（由申请人提供）：冠状动脉疾病的患病率非常高，世界上几乎50%的老年人口缺乏维生素D。低水平的维生素D会增加患心脏病、中风、高血压和糖尿病的风险。球囊血管成形术/支架植入术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。没有数据可以预测哪些患者在冠状动脉介入治疗后会发生内膜增生和支架内再狭窄。本研究的目的是评价维生素D状态对在良好控制的猪动脉粥样硬化模型中进行干预后冠状动脉通畅性结局指标的影响，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内膜增生取决于维生素D状态，补充维生素D可抑制炎症。我们建议利用高血脂和动脉粥样硬化的微型猪模型，用维生素D缺乏、维生素D充足和维生素D补充的饮食喂养。动物将接受球囊血管成形术或血管内支架植入术。目的1中的假设预测，维生素D缺乏将通过增加平滑肌细胞增殖（SMC）和增强炎症来增加冠状动脉介入术后的内膜增生和再狭窄。目标2中的假设预测，维生素D补充将通过减少SMC增殖和抑制炎症来减少冠状动脉介入术后的内膜增生和再狭窄。Aim 3的假说预测维生素D通过抑制炎症和通过抑制importin-3的转录和翻译减少NF-κ B向细胞核的移位来减少平滑肌细胞增殖，从而减少内膜增生和再狭窄。将在冠状动脉介入治疗后6个月内对患有维生素D缺乏、充足和补充的高胆固醇血症和动脉粥样硬化小型猪进行左心室造影和光学相干断层扫描随访，以评估心脏功能并量化节段内最小管腔直径、直径狭窄、晚期损失和内膜增生。此外，血清25-羟基维生素D，炎症介质和细胞因子，血脂和其他生化和临床变量的水平。将对冠状动脉进行内膜厚度、内膜增生、管腔面积、内膜-中膜比、斑块形成和斑块溃疡、再闭塞以及炎性细胞浸润的组织学和免疫组织化学评价。还将检查分离的平滑肌细胞中VDR、CYP 24 A1、CYP 27 B1、NF-κ B、importin-3和prohibitin的mRNA和蛋白表达。这些研究将为我们的假设提供概念支持，并使我们能够评估维生素D补充剂在预防冠状动脉疾病患者冠状动脉介入治疗后临床并发症方面的有效性。