血管平滑肌细胞自噬机制对动脉粥样硬化斑块形成影响及丹皮酚干预作用

项目名称： 血管平滑肌细胞自噬机制对动脉粥样硬化斑块形成影响及丹皮酚干预作用

项目编号： No.81473386

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： 戴敏

作者单位： 安徽中医药大学

项目金额： 73万元

中文摘要： 细胞自噬对炎症有调控作用，是动脉粥样硬化（AS）斑块形成或不稳定的关键性因素。适度自噬可以抑制血管平滑肌细胞（VSMCs）炎症和增殖，而自噬的过度激活会导致细胞自噬样死亡引起斑块破裂，但VSMCs的自噬在AS发生发展中作用及具体调控机制至今鲜有科学依据，相应的药物干预机制研究更是亟待开展。本项目以已结题国家自然基金研究为基础，建立家兔AS模型及血管内皮细胞与平滑肌细胞体外共培养体系，探讨家兔AS模型的不同进程及ox-LDL不同浓度刺激下细胞自噬机制对VSMCs炎症、增殖和凋亡的影响；采用细胞培养、分子生物学、基因沉默和转染等技术研究自噬缺失或过度对PI3K/Akt/mTOR和PI3K/Beclin1通路的影响；同时研究清热解毒中药丹皮的有效成分丹皮酚通过干预自噬而减轻斑块或稳定斑块、发挥抗AS的分子机制，以期为有针对性使用药物治疗以及明确丹皮酚的作用靶点提供科学依据。

中文关键词： 丹皮酚；动脉粥样硬化；血管平滑肌细胞；自噬；信号通路

英文摘要： Cell autophagy, which regulates inflammatory reaction, is a decisive factor of atherosclerosic plaque formation or rupture. Moderate autophagy inhibits inflammation and proliferation of vascular smooth muscle cells, while excessive autophagy leads to rupture of atherosclerotic plaque because of autophagic cell death. However, there is little scientific basis for vascular smooth muscle cells autophagy mechanism in developmental and pathological processes of atherosclerosis, and the corresponding drug intervention research is also extremely urgent. This project establishs a rabbit atherosclerosis model in vivo and a vascular endothelial cells - vascular smooth muscle cells coculture system in vitro based on the finished research of national natural science foundation. The aim is to investigate the processes of rabbit atherosclerosis and the effects of cell autophagy on vascular smooth muscle cells inflammation, proliferation, apoptosis under the stimulus of different concentration of oxidized low density lipoprotein. Cells culture, molecular biology, gene silencing and transfection are performed to explore the effects of autophagy deficiency or excess on PI3K/Akt/mTOR and PI3K/Beclin 1 signaling pathway. Simultaneously, the anti-atherosclerosis mechanisms of paeonol, a main active compound in radix of Cortex Moutan, are elucidated by interfering autophagy to increase plaque stability. This project provides scientific basis for new drug target of paeonol in clinical treatment on atherosclerosis.

英文关键词： Paeonol;Atherosclerosis;Vascular smooth muscle cells;Autophagy;signaling pathway