内皮细胞源性外泌体LncUEDE调控的巨噬细胞活性改变在动脉粥样硬化中的作用及其机制研究

It is very important in the pathogenesis of atherosclerosis that biological mediators derived from injured endothelial cells, such as cytokines, participate as paracrine mediators in regulating macrophage activity. Exosomal bioactive molecules including miRNAs and lncRNAs, as mediators, play important roles in cell to cell interaction. However, to date only limited studies have focused on the interaction of endothelial cells and macrophages via exosomal lncRNAs. Therefore, we designed the present study. We have analyzed the expressions of exosomal lncRNAs between injured endothelial cells and normal endothelial cells by microarray. According to the results, we identified that lncUEDE was highly expressed in exosomes derived from injured endothelial cells comparing to those from normal endothelial cells. Nextly, we would continue to reveal the transmitting mechanism of exosomal lncUEDE from endothelial cells to macrophages. Furthermore, we would investigate the functional regulatory effects and the underlying mechanisms of lncUEDE on macrophages. Additionally, we also planed to explore the potential value of lncUEDE as a new diagnostic biomarker for atherosclerosis disease. Our study would provide theoretical basis for the development of new strategies for the diagnosis and treatment for atherosclerosis.

内皮细胞损伤后以细胞因子等作为介质通过旁分泌方式调控巨噬细胞活性改变是动脉粥样硬化发生的重要机制。外泌体作为媒介携带miRNAs、lncRNAs等多种生物活性分子在细胞间进行信息传递是细胞间交互作用的重要方式。然而，内皮细胞源性外泌体lncRNAs对巨噬细胞活性改变是否具有调控作用尚不清楚。基于此，本研究通过微阵列芯片分析了损伤内皮细胞和正常内皮细胞外泌体中差异lncRNA表达谱，并成功筛选出能够促进巨噬细胞凋亡和脂质积聚的内皮细胞源性外泌体lncUEDE。我们将在此基础上，继续探索外泌体lncUEDE在内皮细胞与巨噬细胞之间传递的具体机制；深入探究lncUEDE对巨噬细胞源性泡沫细胞形成及炎症反应等过程的调控作用及其具体机制；并进一步分析血浆外泌体lncUEDE表达水平作为动脉粥样硬化临床诊断标志物的潜在价值。本研究将为发掘动脉粥样硬化临床诊治的新策略提供理论依据与靶标。

内皮细胞损伤后以细胞因子等作为介质通过旁分泌方式调控巨噬细胞活性改变是动脉粥样硬化发生的重要机制。外泌体作为媒介携带miRNAs、lncRNAs等多种生物活性分子在细胞间进行信息传递是细胞间交互作用的重要方式。本研究拟观察来源于损伤内皮细胞外泌体中lnc-MRGPRF-6:1 (lncUEDE)对巨噬细胞活性的调控作用及其机制。在研究中，我们发现：(1) 敲除lnc-MRGPRF-6:1能够抑制ox-LDL诱导下THP-1巨噬细胞源性泡沫细胞形成，并且能够抑制THP-1巨噬细胞凋亡、增殖及降低细胞氧化应激水平；(2) 敲除lnc-MRGPRF-6:1能够抑制THP-1巨噬细胞M1极化，减少促炎细胞因子的表达与释放；(3) 在THP-1巨噬细胞中lnc-MRGPRF-6:1可能通过TLR4-MyD88-MAPK信号通路调控了巨噬细胞的极化。本研究揭示了损伤内皮细胞源性外泌体lnc-MRGPRF-6:1对巨噬细胞源性泡沫细胞形成及炎症反应等过程的调控作用及其可能的分子机制，为发掘动脉粥样硬化临床诊治的新策略提供理论依据与靶标。