炎症调节内皮素系统诱导血管平滑肌表型转化的机制

项目名称： 炎症调节内皮素系统诱导血管平滑肌表型转化的机制

项目编号： No.81470544

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： 张维

作者单位： 厦门大学

项目金额： 73万元

中文摘要： 炎症状态下血管平滑肌细胞（VSMC）表型转化是动脉粥样硬化的关键因素，内皮素（ET）系统（配体和受体）高表达与之密切相关。我们前期在高脂饮食和脂多糖诱导的炎症动物模型，以及炎症因子刺激下离体动脉和VSMC中发现，ET系统表达显著增加，NF-κB通路激活，表型转化相关基因表达改变；体外阻断NF-κB通路可有效抑制ET系统上调。但炎症调节ET系统的分子机制仍不明确，ET系统调控后对VSMC表型转化的作用和机制尚未得到深入研究。本课题拟借助离体细胞培养模型和在体炎症动物模型研究：1）炎症通过NF-κB通路调节ET系统表达的分子机制；2）ET系统过表达后VSMC表型转化关键基因谱的变化；3）ET系统促进VSMC表型转化所依赖的细胞内信号转导途径。明确炎症通过NF-κB通路上调ET系统，进而影响VSMC表型转化的分子机制，可为动脉粥样硬化的防治策略提供新的思路和理论依据。

中文关键词： 内皮素；受体；炎症；表型转化；核因子-κB

英文摘要： The phenotypic modulation of vascular smooth muscle cells (VSMC) under inflammatory state is a key factor in atherosclerosis, and is closely associated with high expression of endothelin (ET) system (ligand and receptors). In the preliminary study we found that, in high fat diet- and lipopolysaccharide-induced animal model of inflammation, as well as in inflammatory cytokine-stimulated arteries and VSMCs in vitro, the expression of ET system was increased, paralleled with activation of NF-κB pathway and alteration expression of phenotypic modulation-related genes. Blockade of NF-κB pathway in vitro could effectively retard the up-regulation of ET system. However, the molecular mechanisms of inflammation on regulation of ET system still remain unclear, whereas the effects of regulated-ET system on VSMC phenotypic modulation and the mechanisms behind have not yet been deeply studied. The present project planned to investigate the followings by using in vitro cell culture model and in vivo animal model of inflammation: 1) the molecular mechanisms of inflammation on regulation of ET system expression through NF-κB pathway; 2) comprehensive analysis of the alteration of key VSMC phenotypic modulation-related gene profile after over-expression of ET system; 3) the intracellular signal transduction pathways by which ET system promotes VSMC phenotypic modulation. By clarifying the molecular mechanisms of inflammation on up-regulation ET system through NF-κB pathway and subsequent influence on VSMC phenotypic modulation, we could provide new ideas and theoretical basis for the prevention and treatment strategies of atherosclerosis.

英文关键词： endothelin;receptor;inflammation;phenotypic modulation;nuclear factor-κB