基于HIF-1对Angptl4的调控探讨痰瘀同治抗低氧诱导动脉硬化的路径

项目名称： 基于HIF-1对Angptl4的调控探讨痰瘀同治抗低氧诱导动脉硬化的路径

项目编号： No.81473465

项目类型： 面上项目

立项/批准年度： 2015

项目学科： 医药、卫生

项目作者： 王师菡

作者单位： 中国中医科学院广安门医院

项目金额： 72万元

中文摘要： 临床研究证实阻塞性睡眠呼吸暂停（OSAS）的病理因素-慢性间歇性低氧（CIH）增加了心血管疾病的全因死亡率,是动脉硬化的独立危险因素。课题组前期研究发现基于痰瘀同治理论组方的丹蒌片能延缓低氧诱导因子（HIF-1）促发的血脂异常和动脉硬化。我们提出如下假说：丹蒌片通过抑制HIF-1对Angptl4的表达调控，激活LPL,发挥抗CIH诱发动脉硬化的作用。本项目以体内及体外实验相结合，采用低氧环境下ApoE-基因敲除小鼠和HIF-1a+/-转基因小鼠为动物模型，低氧培养 HIF-1a -siRNA转染的3T3-L1细胞，观察不同脂肪组织及成熟脂肪细胞中HIF-1、Angptl4、LPL、VEGF-A基因及蛋白表达,血清脂蛋白及动脉斑块形态学变化,明确丹篓片抗CIH诱发动脉硬化的路径、及其对HIF-1/Angptl4的调控机制；为痰瘀同治早期防治CIH导致的动脉硬化机制及靶点提供原创性研究依据。

中文关键词： 低氧诱导因子-1/血管生成素样蛋白4；低氧；动脉硬化；痰瘀同治；路径

英文摘要： Recent evidence suggests that Obstructive sleep apnea syndrome(OSAS) is a highly prevalent disease with increased all-cause and cardiovascular mortality characterized by chronic intermittent hypoxia (CIH). OSAS was already shown as an independent risk factor for atherosclerosis. We have previously noticed that the atherosclerotic and dyslipidemia of the patients with OSA could be attenuated by the treatment of Danlou tablet which can eliminate phlegm and promote blood circulation. We hypothesized that the mechanism of Danlou tablet on OSAS was through the pathway of Angptl4 and LPL regulated by HIF-1.We tested our hypotheses by treating CIH-exposed, ApoE-knockout mice and HIF-1a overpressing mice using advanced technologies in modern bioinformatics and biology to exam the different adipose Angptl4、LPL、VEGF-A mRNA and protein expression, serum lipoproteins level and arteroma morphology changes from structure and function aspects to verify the hypothesis. Through 3T3-L1 cells transfection, we will test Angptl4 could be abolished by Danlou tablet. This original research should be explain the mechanism of CIH induced atherosclerosis and dyslipidemia after Doulan treatment.

英文关键词： HIF-1/ANGPTL4;Hypoxia;Atherosclerosis;Simultaneous treatment for phlegm and stasis;Pathway