提高血流剪切应力抑制早期动脉粥样硬化及调控炎症相关基因的研究

项目名称： 提高血流剪切应力抑制早期动脉粥样硬化及调控炎症相关基因的研究

项目编号： No.30871047

项目类型： 面上项目

立项/批准年度： 2009

项目学科： 生物科学

项目作者： 张焰

作者单位： 中山大学

项目金额： 30万元

中文摘要： 我国动脉粥样硬化性疾病的发病率呈上升趋势且发病年龄提前，使早期防治日益重要。高脂血症等危险因素可触发炎症反应导致内皮功能障碍。动脉粥样硬化病变好发于血流剪切应力明显降低且方向紊乱处。提高血流剪切应力是保护血管内皮细胞，调动内皮损伤修复的关键环节。本课题细胞培养部分，研究不同剪切应力对ox-LDL诱导的内皮细胞炎症损伤及相关基因的影响，初步发现生理范围内较高水平的剪切应力作用于人脐静脉内皮细胞能减轻ox-LDL造成的病理形态学损害。高脂饮食造早期动脉粥样硬化猪模型，采用EECP长期提高脉动血流剪切应力干预，用病理、电镜、分子生物学等方法观察各组病变及炎症相关基因表达的差异。发现长期EECP能够减轻高脂喂饲造成的早期动脉粥样硬化，抑制血管炎症反应，其机制与抑制高脂血症引发的MAPK-P38/NF-kB/VCAM-1信号转导途径的过度激活有关。进而观察用EECP长期提高人体脉动血流剪切应力对高脂血症合并亚临床动脉粥样硬化患者的作用。本课题从细胞培养、动物实验、人体实验三个层次深入探讨血流剪切应力对早期动脉粥样硬化的影响及其炎症相关分子机制，为防治动脉硬化提供了一项有效的无创策略。

中文关键词： 动脉硬化；内皮;血管；应力;物理；炎症；反搏动术

英文摘要： It is now very important that atherosclerosis should be prevented in early stage. It has been shown that atherosclerotic lesions preferentially develop at arterial bifurcations which are regions of disturbed flow or low shear stress. Physiological shear stress at a relatively high level has an vasoprotective effect. In the present study, endothelial cells were cultured to study the effect of different shear stress on ox-LDL induced inflammation.The results showed that physiological shear stress at a relatively high level help to repair endothelial cell damage induced by ox-LDL. Then, early atherosclerosis was developed in a porcine model. Enhance External Counterpulsation(EECP) intervention was used as a means to increase shear stress in vivo and its hemodynamic effects were proven by untrasound examination. The results showed that the chronic exposure to increased pulsatile shear stress promted by EECP exerts a retarding effect on atherosclerosis by downregulating proinflammmatory gene expression. The underlying mechanisms are related to this exposure suppresses the overactivation of the MAPK-P38/NF-kB/VCAM-1 signaling pathway induced by hypercholesterolemia. Clinical trial was designed to examine the effects of EECP on subclinical atherosclerosis associated with hypercholesterolemia. The present study investigated the effect of increased shear stress on early athrosclerosis and its inflammation related molecualr mechanisms, suggesting a new therapeutic strategy for the prevention and treatment of atherosclerotic disease.

英文关键词： athrosclerosis; endothelium; shear stress; inflammation;External counterpulsation;