髓过氧化物酶在皮肌炎血管损伤中的作用及机制

Vascular injury plays an important role in the pathogenesis of dermatomyositis (DM). Myeloperoxidase (MPO) is crucial in promoting vascular endothelial cells apoptosis, affecting vascular function and inducing vascular injury, but its functions in vascular injury in DM are not clear. Our previous study found the expression of MPO mRNA is increased in the peripheral blood mononuclear cells of DM via microarray analysis and real-time PCR; it is hypomethylation in DM via DNA methylated microarray and pyrophosphate sequencing; the serum concentration of MPO is increased. Incubation with DM serum, the activity and the ability of tube-forming of endothelial cells are decreased, and the permeability of cells is increased. We hypothesize that MPO could promote vascular injury and participate in the pathogenesis of DM. In this study, we will first detect the expression and activity of MPO and confirm the secretory cells. Further, we will study the role of MPO in vascular injury and related mechanism. Then we will construct recombinant human skeletal C-protein induced experimental autoimmmune myositis mice and explore the possibility of intervening MPO in the treatment of disease. This study will help to elucidate the pathogenesis of DM and provide new theoretical basis for the treatment of DM.

血管损伤在皮肌炎（DM）的发病中具有重要作用。髓过氧化物酶（MPO）具有促进血管内皮细胞凋亡，影响血管功能，促进血管损伤的作用，但其在DM血管损伤中的作用未见报道。申请者前期利用芯片和PCR/焦磷酸盐测序发现MPO在DM外周血单个核细胞中呈明显高表达，低甲基化水平；血清中MPO的浓度增高；内皮细胞经DM血清孵育后活性降低，成管能力下降，通透性增加。因此提出“MPO通过促进血管损伤参与DM发生发展”的假说。本项目首先明确MPO的表达部位、活性和细胞来源，从细胞水平研究MPO在血管损伤中作用及机制。构建人骨骼肌C蛋白诱导的动物模型，探讨干预MPO治疗疾病的可能性。为阐明皮肌炎的发病机制并以MPO为靶点进行治疗提供新的理论依据。

皮肌炎（Dermatomyositis, DM）是一种主要累及皮肤、肌肉和血管的炎症性自身免疫病，皮肌炎的肌肉病理主要表现为束周萎缩和束周血管炎等，但引起该病理表现的机制目前尚不清楚。髓过氧化物酶（Myeloperoxidase, MPO）具有促进血管内皮细胞凋亡，影响血管功能，促进血管损伤的作用，但其在皮肌炎发病中的作用未见报道。本课题组利用芯片和PCR/焦磷酸盐测序发现MPO在DM外周血单个核细胞中明显高表达，低甲基化，肌肉组织中MPO主要表达于皮肌炎束周血管及束周萎缩部位，主要表达于浸润的CD4+细胞、CD8+细胞、CD68+细胞。DM患者血清中MPO的浓度增高，且与外周血白细胞计数、血清中肌酸激酶的水平正相关。用MPO刺激人皮肤微血管内皮细胞可使细胞活性明显下降，细胞成管能力明显下降，对外周血单个核细胞的通透性明显增加，内皮细胞间粘附分子1、血管细胞粘附因子1、E-选择素的mRNA表达上调。用MPO刺激人肌成纤维细胞后肌萎缩相关分子Atrogin-1 mRNA及蛋白表达均明显增加。综上，本课题表明MPO在DM患者外周血单个核细胞和肌肉组织中表达增加，且通过促进粘附分子、E-选择素的表达增加炎症细胞的迁移，通过降低血管内皮细胞的活性增加血管对炎症细胞的通透性，且MPO通过增加Atrogin-1的表达在肌肉萎缩的过程中发挥一定作用。本研究初次探究了MPO在DM发病机制中的作用，为阐明皮肌炎的发病机制并以MPO为靶点进行治疗提供了新的依据。