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: 8843943
• 负责人: Devendra K. Agrawal
• 金额: $ 68.49万
• 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 2016-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8843943
• 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; Health; 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，世界上近 50% 的老年人缺乏维生素 D。维生素 D 水平低会增加患心脏病、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会出现内膜增生和内膜增生。本研究的目的是评估维生素 D 状态对动脉粥样硬化控制良好的猪模型进行干预后冠状动脉通畅的结果测量的影响，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 状态，补充维生素 D 可以抑制炎症，我们建议利用饲喂维生素的高脂血症和动脉粥样硬化微型猪模型。 D 缺乏、维生素 D 充足和补充维生素 D 的饮食 动物将接受球囊血管成形术或血管内支架植入术。目标 1 中的假设预测，维生素 D 缺乏会通过增加平滑肌细胞来增加冠状动脉介入治疗后的内膜增生和再狭窄。目标 2 中的假设预测，补充维生素 D 将通过减少 SMC 增殖和增强炎症来减少冠状动脉介入治疗后的内膜增生和再狭窄。目标 3 的假设预测，维生素 D 通过抑制炎症和通过抑制输入蛋白-¿ 的转录和翻译减少 NF-kB 向细胞核的易位来减少平滑肌细胞增殖，从而减少内膜增生和再狭窄。 3. 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微型猪，将在冠状动脉介入治疗后六个月内进行左心室造影和光学相干断层扫描，以评估心脏功能并量化节段内最小管腔直径、直径狭窄、晚期此外，还包括 25-羟基维生素 D、炎症介质和细胞因子、血脂等的血清水平。还对冠状动脉的内膜厚度、内膜增生、管腔面积、内膜-中膜比率、斑块发展和斑块溃疡以及再闭塞和炎症细胞浸润进行组织学和免疫组织化学评估。和 VDR、CYP24A1、CYP27B1、NF-kB、importin-¿ 的蛋白表达3，将检查分离的平滑肌细胞中的抑制素，这些研究将为我们的假设提供概念支持，并使我们能够评估补充维生素 D 在预防冠状动脉疾病患者干预后临床并发症方面的有效性。