ApoA1/ABCA1抗动脉粥样硬化新机制-自噬介导的血管外周脂肪组织抗炎途径

项目名称： ApoA1/ABCA1抗动脉粥样硬化新机制-自噬介导的血管外周脂肪组织抗炎途径

项目编号： No.81470569

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： 尹凯

作者单位： 南华大学

项目金额： 72万元

中文摘要： 近来研究发现血管外周脂肪组织(PVAT)炎症诱发的血管外膜反应在动脉粥样硬化(As)血管重构中起着关键作用。我们前期发现载脂蛋白AI（apoAI）及其受体ABCA1具有抑制血管内膜炎症的效应，但其在PVAT和血管外膜病理生理中的作用尚不明确。结合前期结果和文献，本课题提出apoAI/ABCA1调节PVAT自噬/NLRP3炎性体激活抑制PVAT炎症抗As的假说,拟证实:①apoAI/ABCA1通过JAK2/STAT3/PKR/eIF2α信号途径上调PVAT自噬，抑制棕榈酸刺激PVAT脂肪细胞NLRP3炎性体激活和炎症反应；②经PVAT过表达apoAI抑制高脂饮食球囊损伤颈动脉小型猪As血管重构、PVAT炎症，上调自噬、抑制NLRP3炎性体激活和血管外膜成纤维细胞增殖/分化。本项目有望阐明apoAI/ABCA1对PVAT炎症的作用和机制，为As和血管成形术后再狭窄的防治提供新的思路和靶点。

中文关键词： 动脉粥样硬化；载脂蛋白A-I；血管外周脂肪组织；炎症；自噬

英文摘要： The emerging evidences have demonstrated that adventitia response induced by perivascular adipose tissue(PVAT) inflammation plays a crucial role in the development of atherosclerosis(As)-related vascular reconstruction. The previous studies performed by our group have shown that apolipoprotein A1(apoA1) can inhibit the inflammation of arterial intima.The exact pathophysiologic effect and mechanism of apoA1/ABCA1 in PVAT and vascular adventitia,however,are still unclear.We hypothesize that inflammatory phenotype of PVAT is attenated by apoA1/ABCA1 pathway via inducing autophagy- mediated NLRP3 inflammasome deactivation that leads to the inhibition of PVAT inflammation and atherosclerosis. This proposed project will firstly confirm that apoAⅠ/ABCA1 suppresses pro-inflammatory cytokines secretion in primary adipocyte from PVAT through inducing autophagy and inhibiting activation of NLRP3 inflammasome via JAK2/STAT3/PKR/eIF2α-dependent manner.Then, we will further verified that PVAT- specific overexpression of apoAⅠ in minipigs treated by high-fat diet and balloon hyperinflation in carotid artery intima will decrease the inflammatory phenotype of PVAT including suppressing the infiltration of inflammatory cells and secretion of pro-inflammatory cytokines, upregulate adipocyte autophagy, inhibit NLRP3 inflammasom activation as well as the adventitial fibroblast proliferation/ differentiation and this will correlate with decreased development of atherosclerosis.The proposed studies will provide conceptual and mechanism support for the effect of apoA1/ABCA1 on the PVAT inflammation and position us to translate our investigation into a clinical study for anti-atherosclerosis and anti-restenosis therapy after angioplasty.

英文关键词： atherosclerosis;apolipoprotein A-I;perivascular adipose tissue;inflammation;autophagy