microRNA155在动脉粥样硬化发生过程中的网络调控机制

The network regulation mechanism of microRNA 155 in the development of atherosclerosis

动脉粥样硬化(atherosclerosis,AS)是一种慢性进行性的血管炎症性疾病,其发病机制主要包括内皮细胞损伤,脂质浸润及炎症介质分泌等。microRNA155(miR-155)是参与AS炎性调控、免疫和自噬信号等通路的微小非编码RNA。系统性研究miR-155及其靶基因的网络调控机制,能全面理解miR-155在AS中的作用,促进其在临床诊断中的应用开发。利用miRNA靶基因预测数据库miRDB、miRmap和Starbase获取miR-155的靶基因集。R语言分析基因表达综合数据库(gene expression omnibus,GEO)共享平台动脉粥样硬化斑块差异表达基因(GSE24702),筛选出18076个差异表达基因。利用基因集富集分析(gene set enrichment analysis,GSEA)分析,观察这些差异表达基因共同富集在IL6-JAK-STAT3信号通路、炎症反应和TNFα等炎症信号通路。与miR-155靶基因交叉匹配得到371个交集mRNA,其中159个在动脉粥样硬化斑块中上调,212个在动脉粥样硬化斑块中下调。基因本体(gene ontology,GO)及基因组数据库(kyoto encyclopedia of genes and genomes,KEGG)分析研究基因功能,GO富集分析371个差异基因主要富集炎症和凋亡信号通路的负调控等功能,KEGG分析371个差异基因主要富集TGFβ等炎症信号通路。蛋白相互作用网络(protein-protein interaction networks,PPI)分析获得关键节点基因是ARRB2、FBXO11、SOCS1、FBXO22、FBXO30、KRAS、RNF19A、TRIM32、HERC4、PJA1、RCHY1和DET1。本研究表明,miR-155主要通过调控炎症反应等相关信号通路影响斑块细胞炎症、自噬及凋亡等功能,进而影响动脉粥样硬化的各个进程。

Atherosclerosis(AS)is a chronic and progressive vascular inflammatory disease.Its pathogenesis mainly includes endothelial cell injury,lipid infiltration and secretion of inflammatory mediators.microRNA155(miR-155)is a small non-coding RNA involved in inflammatory regulation,immune and autophagy signaling of AS.Systematic study on the network regulation mechanism of miR-155 and its target genes can fully understand the role of miR-155 in AS and promote its application in clinical diagnosis.The target gene set of miR-155 was obtained by using miRNA target gene prediction databases miRDB,miRmap and Starbase.R language was utilized to analyze the differentially expressed genes in atherosclerotic plaques in GEO(GSE24702),18076 differentially expressed genes were screened.GSEA analysis were used to observe that these differentially expressed genes were co-enriched in IL6-JAK-STAT3 signaling pathway,inflammatory response and TNFαand other inflammatory signaling pathways.371 overlapping mRNA were achieved by crossmatching with miR-155 target genes,of which 159 were up-regulated in atherosclerotic plaques and 212 were down-regulated in atherosclerotic plaques.The function of genes was studied by GO and KEGG analysis,GO enrichment analysis of 371 differential genes mainly enrich the negative regulation of apoptosis signal pathway and inflammatory response,etc.KEGG analysis of 371 differential genes mainly enrich TGFβand other inflammatory signal pathways.PPI analysis showed that the key genes were ARRB2,FBXO11,SOCS1,FBXO22,FBXO30,KRAS,RNF19 A,TRIM32,HERC4,PJA1,RCHY1 and DET1.This study indicated that miR-155 may affect the functions of plaque cell inflammation,autophagy and apoptosis through the regulation of inflammatory response and other related signal pathways,and then affecting the processes of atherosclerosis.