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

• 批准号: 8600755
• 负责人: Devendra K. Agrawal
• 金额: $ 67.61万
• 依托单位: CREIGHTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-07-23 至 2018-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8600755
• 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; Functional disorder; 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; Vasodilation; Vitamin D; Vitamin D Deficiency; X-Ray Computed Tomography; adipokines; adiponectin; animal facility; arginase; chemokine; cytokine; dietary supplements; feeding; intima media; mRNA Expression; macrophage; p65; prohibitin; protein expression; public health relevance; resistin; response to injury; restenosis; subcutaneous; vascular inflammation

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层心肌附近，作为内分泌器官和炎症组织，分泌激素、细胞因子和趋化因子。由于动脉粥样硬化病变是由炎症和细胞外基质形成引起的，而炎症和细胞外基质的形成被肥胖夸大了，因此肥胖动脉粥样硬化患者采取相反的干预措施后，预后很差。我们假设，冠状动脉介入治疗后，维生素D缺乏导致内皮功能障碍和内膜增生加剧，从而加剧了肥胖引起的心外膜脂肪炎症表型。目的1：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，并伴随冠状动脉介入治疗后冠状动脉血管舒张功能受损，增加心血管事件的复发率。目的2：我们的假设预测维生素D缺乏会加剧，补充维生素D会减少EAT的厚度和炎症表型，恢复冠状动脉血管舒张，这将与冠状动脉介入治疗后心血管事件的复发率降低相关。目的3：我们的假设预测肥胖和动脉粥样硬化猪的EAT炎症表型的增强是由于NF-？B通过增加输入蛋白-¿3的转录和翻译，减少禁止蛋白和SOCS3传递到细胞核，维生素D抑制EAT的促炎反应。高果糖饮食的高胆固醇血症猪将接受球囊血管成形术和支架植入术。在高胆固醇和高果糖饲粮中研究维生素D缺乏、充足和补充的猪对维生素D的影响。心外膜脂肪厚度将通过心脏CT测量。血管造影和光学相干断层扫描将评估心功能，量化节段内最小管腔直径和内膜增生。内皮依赖性和非依赖性冠状动脉血管舒张将通过冠状动脉内给药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/M2巨噬细胞极性、t淋巴细胞亚群、促炎和抗炎介质及细胞因子水平的变化。组织学上，将检查内膜厚度和内膜增生、管腔面积、内膜-中膜比、斑块发展和再闭塞。拟议的研究将为我们的假设提供概念支持，并使我们将我们的研究转化为肥胖冠状动脉疾病患者的临床研究。