EPICARDIAL ADIPOSE TISSUE, OBESITY AND INFLAMMATION IN ATHEROSCLEROSIS

动脉粥样硬化中的心外膜脂肪组织、肥胖和炎症

基本信息

批准号：
8775002
负责人：
Devendra K. Agrawal
金额：
$ 2.58万
依托单位：
CREIGHTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-01-01 至 2018-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8775002
关键词：
Acetylcholine Address Adenosine Adipocytes Adipose tissue Angiography Angioplasty Anterior Anti-Inflammatory Agents Anti-inflammatory Area Arterial Fatty Streak Arteries Atherosclerosis Balloon Angioplasty Biochemical Blood Vessels CCL2 gene Caliber Cardiac Cardiovascular system Cell Nucleus Cell Proliferation Cholesterol Chronic Clinical Research Coronary Coronary Arteriosclerosis Coronary artery Deposition Development Diet Disease Endocrine Glands Endothelium Event Exposure to Extracellular Matrix Family suidae Fatty acid glycerol esters Fructose Genetic Transcription Health Heart Histologic Hormones Housing Human Hyperplasia IL2RA gene ITGAX gene Immune response Impairment Importins Inflammation Inflammation Mediators Inflammatory Inflammatory Response Insulin Resistance Interferons Interleukin-10 Interleukin-17 Interleukin-6 Intervention Investigation Left Leptin Lighting Lymphocyte Measurement Measures Mediating Metabolic Modeling Molecular Myocardium Nerve Tissue Obesity Optical Coherence Tomography Outcome Pathogenesis Patients Phenotype Population Positioning Attribute Prevalence Regulatory T-Lymphocyte Stenosis Stents Sunlight Supplementation Surface T-Lymphocyte Subsets TNF gene Testing Thick Tissues Torsion Translating Translations Tunica Adventitia Ulcer Vascular Diseases Vasodilation Vitamin D Vitamin D Deficiency X-Ray Computed Tomography adipokines adiponectin animal facility arginase chemokine cytokine dietary supplements endothelial dysfunction feeding intima media mRNA Expression macrophage p65 prohibitin protein expression resistin response to injury restenosis subcutaneous

项目摘要

DESCRIPTION (provided by applicant): Epicardial adipose tissue (EAT) is present in close proximity to the adventitia of the coronary arteries and the underlying myocardium, and functions as both endocrine organ and inflammatory tissue, secreting hormones, cytokines and chemokines. Since atherosclerotic lesions result from inflammation and extracellular matrix formation that are exaggerated by obesity, there is a poor outcome in obese atherosclerotic patients following contrary intervention. We hypothesize that obesity-induced inflammatory phenotype of epicardial fat is exacerbated by vitamin D deficiency leading to endothelial dysfunction and enhanced intimal hyperplasia following coronary intervention. Aim 1: Our hypothesis predicts that high fructose and high fat diet will increase thickness and the inflammatory phenotype of EAT accompanied with impairment of coronary vasodilatation and increased reoccurrence of cardiovascular events following coronary artery intervention. Aim 2: Our hypothesis predicts that vitamin D deficiency will exacerbate and vitamin D supplementation will decrease thickness and the inflammatory phenotype of EAT and restore coronary vasodilatation and this will correlate with decreased reoccurrence of cardiovascular events following coronary artery intervention. Aim 3: Our hypothesis predicts that enhanced inflammatory phenotype of EAT in obese and atherosclerotic swine is due to increased translocation of NF-?B to the nucleus via increased transcription and translation of importin-¿3 and decreased prohibitin and SOCS3, and vitamin D suppresses pro-inflammatory responses in EAT. Hypercholesterolemic swine on high fructose diet will undergo balloon angioplasty and stenting. Effect of vitamin D will be examined in vitamin D-deficient, -sufficient and supplemented swine fed with high cholesterol and high fructose diet. Epicardial fat thickness will be measured by cardiac CT. Angiogram and Optical Coherence Tomography will be done to assess cardiac function and quantify in-segment minimal luminal diameter and intimal hyperplasia. Endothelium-dependent and -independent coronary vasodilatation will be measured by intracoronary administration of adenosine and acetylcholine. Biochemical parameters in epicardial fat will include the changes in adipocyte size, M1/M2 macrophage polarity, T-lymphocyte subsets, levels of pro- and anti-inflammatory mediators and cytokines. Histologically, intimal thickness and intimal hyperplasia, lumen area, intima-media ratio, plaque development, and re-occlusion will be examined. The proposed studies will provide conceptual support of our hypothesis and position us to translate our investigation into a clinical study in obese patients with coronary artery disease.

描述（由申请人提供）：心外膜脂肪组织（EAT）存在于冠状动脉外膜和下面的心肌附近，具有内分泌器官和炎症组织的功能，在动脉粥样硬化病变时分泌激素、细胞因子和趋化因子。由于肥胖导致炎症和细胞外基质形成加剧，因此我们发现肥胖引起的动脉粥样硬化患者的预后较差。维生素 D 缺乏会加剧心外膜脂肪的炎症表型，导致冠状动脉介入治疗后内皮功能障碍和内膜增生增强。我们的假设预测，高果糖和高脂肪饮食会增加 EAT 的厚度和炎症表型，并伴有冠状动脉损伤。目标 2：我们的假设预测维生素 D 缺乏会恶化，补充维生素 D 会减少冠状动脉的厚度和炎症表型。 EAT 并恢复冠状血管舒张，这与冠状动脉介入治疗后心血管事件的复发率降低相关。目标 3：我们的假设预测肥胖和动脉粥样硬化猪中 EAT 炎症表型的增强是由于 NF-κB 向细胞核的易位增加所致。通过增加 importin-¿ 的转录和翻译3 和抑制素和 SOCS3 的减少，以及维生素 D 抑制高果糖饮食的高胆固醇血症猪的促炎反应，将在维生素 D 缺乏、维生素 D 充足和补充的猪中检查维生素 D 的效果。高胆固醇和高果糖饮食将通过心脏血管造影和光学相干断层扫描来测量心外膜脂肪厚度。为了评估心脏功能并量化节段内最小管腔直径和内皮依赖性和非依赖性冠状血管舒张，将通过冠状动脉内施用腺苷和乙酰胆碱来测量心外膜脂肪的生化参数，包括脂肪细胞大小、M1/的变化。 M2 巨噬细胞极性、T 淋巴细胞亚群、促炎和抗炎介质以及细胞因子的水平。将检查内膜厚度和内膜增生、管腔面积、内膜中膜比例、斑块发育和再闭塞，拟议的研究将为我们的假设提供概念支持，并使我们能够将我们的研究转化为肥胖患者的临床研究。冠状动脉疾病。