PEAT调控胰岛素抵抗诱导的冠脉粥样硬化的机制研究

Coronary heart disease is a kind of the cardiovascular disease with highest mortality in the world, the vicious cycle between vascular endothelial dysfunction and insulin resistance (IR)is the key link in its development. Pericardial epicardial adipose tissue (PEAT) plays an important role in the regulation of IR-induced coronary atherosclerosis (CA). Our previous study has found that omentin-1 secreted by PEAT can inhibit vascular endothelial cell injury and insulin resistance . In insulin resistance patients, PEAT hypertrophy, increased white / beige fat ratio, local inflammatory infiltration and decreased omentin-1 and adiponectin expression were noted. Therefore, we speculate that IR may change the structure of PEAT, inhibit the expression of beneficial adipokines, induce chemotaxis and polarization of macrophages and aggravate coronary lesions. If the ratio of white / beige fat in PEAT is decreased, the adverse effects of IR can be reduced,contributing to coronary protection. This study intends to use organ slice culture, molecular biology and cell biology techniques, combined with in vitro cell models and animal experiments to study the specific mechanisms of IR-induced PEAT remodeling, and the regulation of PEAT-related adipokines on coronary artery, in order to find The possibility of fat-remodeling gene therapy and to provide new ideas and theoretical basis for the treatment of patients with coronary heart disease complicated with IR.

冠心病是病死率最高的心血管疾病，血管内皮功能紊乱和胰岛素抵抗（IR）间的恶性循环是其发生发展的关键环节。围冠脉心外膜脂肪（PEAT）在调控IR诱导的冠脉粥样硬化的过程中发挥重要作用。我们前期研究发现PEAT分泌的omentin-1可抑制血管内皮细胞损伤及IR；而IR患者会出现PEAT肥大、白色/米色脂肪比例增高，致局部炎症浸润、omentin-1及adiponectin的表达降低。据此我们推测IR可能会改变PEAT的结构，抑制有益脂肪因子表达，诱导巨噬细胞趋化与极化，加重冠脉损伤；若降低PEAT中白色/米色脂肪比例，能减轻IR的不利影响，达到冠脉保护作用。本研究拟采用器官切片培养、分子生物学和细胞生物学技术，结合体外细胞模型和大动物实验，研究IR诱导PEAT重构的具体机制，及PEAT相关脂肪因子对冠脉的调控作用，以期找到脂肪改造的基因治疗方法，为冠心病合并IR的治疗提供新思路和理论基础。

随着社会的发展及生活方式的改变，冠心病（CAD）在我国的患病率不断上升，严重威胁人民健康。CAD的主要病理表现为冠脉粥样硬化，2型糖尿病（T2DM）为诱发或加重冠脉粥样硬化的重要危险因素。本项目旨在阐明心外膜脂肪（EAT）在T2DM诱发或加重CAD的进程中扮演的角色，以及通过PRDM16过表达“改造”脂肪缓解动脉炎症的可能性。首先我们发现伴随T2DM CAD患者EAT内巨噬细胞浸润增加而omentin-1等脂肪因子表达降低；炎症环境可抑制脂肪前体细胞分化及omentin-1等脂肪因子表达；随后的功能探究表明omentin-1具有缓解内皮炎症损伤的作用。体外及体内实验显示过表达PRDM16可显著上调脂肪细胞/组织内omentin-1等抗炎脂肪因子的表达，抑制炎症因子的表达，并有明显的促脂肪棕色化作用。最后，我们通过细胞共培养及脂肪移植模型进一步探究PRDM16过表达后脂肪功能改变对内皮细胞/动脉的影响，结果显示过表达PRDM16后脂肪因子分泌的变化可有效抑制内皮/动脉炎症。本研究阐明了T2DM状态下EAT的炎症激活及脂肪因子表达改变可能是引发或加重CAD的重要诱因，而利用过表达PRDM16调节脂肪因子表达可有效抑制内皮/动脉炎症。上述结果指出，通过调节EAT功能治疗CAD存在可能。

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