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: 8705012
• 负责人: Devendra K. Agrawal
• 金额: $ 75.15万
• 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/8705012
• 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; public health relevance; resistin; response to injury; restenosis; subcutaneous

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（由适用提供）：心外膜脂肪组织（EAT）与冠状动脉和潜在的心肌的外膜相近，并作为内分泌器官和炎症组织起作用，分泌激素，细胞因子和趋化因子和趋化因子。由于动脉粥样硬化病变是由于肥胖症夸大的感染和细胞外基质形成引起的，因此相反干预后肥胖的动脉粥样硬化患者的预后较差。我们假设肥胖引起的心外膜脂肪的炎症表型因维生素D缺乏而加剧，导致冠状动脉干预后内皮功能障碍并增强内膜增生。目的1：我们的假设预测，高果糖和高脂肪饮食将增加厚度和EAT的炎症表型伴随着冠状动脉血管扩张的损害，并增加了心血管事件的重新发生。血管舒张及其将与冠状动脉干预后心血管事件的重新发生相关。目标3：我们的假设预测，即肥胖和动脉粥样硬化猪的炎症表型增强的预测是由于Nf-？B易位通过增加的转录和进口量3的转录和改善的禁止和SOCS3和SOCS3的转化，而维生素D抑制了饮食中的炎性反应。高果糖饮食上的高胆固醇猪会经历气囊血管成形术和支架。维生素D的作用将在维生素D缺乏剂中检查 - 充满糖脂和高果糖饮食的猪。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进行评估心脏功能并量化段内的最小腔直径和内膜增生。内皮依赖性和非依赖性冠状动脉血管扩张将通过肾上腺内给药和乙酰胆碱的施用来测量。心外膜脂肪中的生化参数将包括脂肪细胞大小的变化，M1/M2巨噬细胞极性，T-淋巴细胞亚群，促和抗炎介质和细胞因子的水平。在组织学上，将检查在组织学上，内膜厚度和内膜增生，管腔区域，内膜媒体比，斑块发育和重新批准。拟议的研究将为我们的假设提供概念上的支持，并将我们的研究转化为肥胖的冠状动脉疾病患者的临床研究。