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

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.

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。

近年来随着代谢综合征和肥胖人群的迅猛增加，动脉粥样硬化（As）相关心血管疾病的发病率和死亡率正逐年升高。载脂蛋白AⅠ（apoA-1）是血浆高密度脂蛋白（HDL）的最主要成分，流行病学研究显示肥胖和冠心病人群的apoA-1水平明显降低，并与心血管疾病的风险呈负相关，但其调控As的机制尚不清楚。本项目建立高脂高糖饮食（HFSD）喂养的肥胖小型猪模型，发现HFSD促进血管重构和动脉粥样硬化（As）的发生发展。本项目首次发现NLRP3炎性体/ IL-1介导的PVAT功能障碍通过调控血管外膜成纤维细胞（AF）增殖和分化，促进肥胖小型猪血管损伤后重构和As的发生发展；在体外，发现apoA-1能够显著抑制转化生长因子β（TGFβ）诱导的内皮间质转化（EndMT）；发现体内维生素D水平与血浆高密度脂蛋白（HDL）水平密切相关，并通过调控胆固醇流出途径影响HDL生成和As的发生发展。本项目研究还发现球囊损伤后的早期阶段，小型猪颈动脉外膜就存在早期损伤反应，提示HFSD诱导的PVAT功能障碍至少在血管外膜重塑的早期阶段具有至关重要的作用。由于小型猪的心血管解剖和代谢生理学与人类极为相似，因此该发现对于明确人类血管损伤的病理生理机制具有重要的意义，而且为抑制As和血管损伤后再狭窄提供了一种新的防治策略。同时，本项目通过血管介入手段，在血管外膜过表达apoA1，经western-blot和免疫组化等方法证实apoA1在PVAT过表达，并显著抑制HFSD喂养的肥胖小型猪血管损伤后重构。在本项目实施过程中，已发表相关论文10篇（SCI收录9篇），获得湖南省自然科学二等奖1项，申报国家发明专利4项（已授权1项），参加国内外学术会议10次（其中大会报告2次，壁报和青年论文竞赛8次）。