心肌纤维化关键基因与通路的研究及有效中药预测

Study on key genes and pathways of myocardial fibrosis and prediction of effective traditional Chinese medicine

目的:应用生物信息学方法筛选心肌纤维化(myocardial fibrosis)的关键基因,探讨其发病机制并预测治疗心肌纤维化的潜在中药。方法:基于基因表达数据库(GEO)中的基因芯片GSE59437原始数据,其中纳入了3例对照组小鼠和3例使用血管紧张素Ⅱ诱导的心肌纤维化小鼠心肌组织样本。使用R语言处理数据并筛选表达显著差异基因(DEG),使用DAVID数据库和R语言对差异基因进行基因本体论(GO)注释以及京都基因与基因组百科全书(KEGG)通路富集,利用STRING数据库构架蛋白蛋白互作(PPI)网络,利用Cytoscape软件进行可视化并利用MCODE插件筛选网络中的关键功能模块。利用医学本体信息检索平台(coremine medical)对关键基因进行映射,构建基因-中药网络,并筛选治疗心肌纤维化的中药。结果:经过筛选获得208个DEGs,其中94个为上调,114个为下调。DEGs主要参与了细胞外基质重构、胶原纤维沉积和脂质代谢紊乱等多种生物过程,KEGG通路富集涉及血小板活化、催产素信号通路、胰岛素分泌、ECM受体相互作用、GnRH信号通路、肿瘤坏死因子信号通路等信号通路。PPI网络的关键模块包括:结缔组织生长因子(CTGF)、金属蛋白酶抑制剂1(TIMP1)、分泌型磷蛋白1(SPP1)、纤溶酶原激活物抑制剂1(SERPINE1)、胶原α1(Ⅲ)链(COL3A1)、骨膜素(POSTN)、原癌基因c-FOS(FOS)7个基因。筛选得到治疗心肌纤维化的潜在中药为:黄芪、葶苈子、丹参。结论:心肌纤维化是一个复杂的病理过程,细胞外基质合成与降解失衡、胶原纤维过度沉积等有关的基因在此过程中发挥着重要作用,本研究为进一步探索心肌纤维化的发病机制,寻找治疗靶点以及潜在的治疗中药提供了科学借鉴。

Objectives:To screen the key genes of myocardial fibrosis,explore its pathogenesis and predict the potential traditional Chinese medicines for the treatment of myocardial fibrosis by applied bioinformatics. Methods:Based on raw data of gene chip GSE59437 from gene expression database(GEO),myocardial tissue samples from 3 control mice and 3 mice treated with angiotensin Ⅱ-induced myocardial fibrosis were included. R language was used for processing data and screening of gene express significant differences(DEG). DAVID datebase and the R language was used to finish gene ontology(GO)annotation and Kyoto encyclopedia of genes and genomes(KEGG)pathway enrichment for differences gene.STRING database was used to structure protein protein interactions(PPI)networks. Cytoscape software was applied for visualization and the MCODE plug-in was used for screening key function modules in the network. Coremine Medical database was used to map the key genes,construct the gene-Chinese medicine network,and screen the traditional Chinese medicines for the treatment of myocardial fibrosis. Results:A total of 208 DEGs were screened,94 of which were up-regulated and 114 were down-regulated. DEGs were mainly involved in a variety of biological processes such as extracellular matrix remodeling,collagen fiber deposition and lipid metabolism disorders.KEGG pathway enrichment involves platelet activation,oxytocin signaling pathway,insulin secretion,ECM-receptor interaction,GnRH signaling pathway,TNF signaling pathway and other signaling pathways. Key modules of PPI network include:CTGF,TIMP1,SPP1,SERPINE1,COL3A1,POSTN and FOS. The potential traditional Chinese medicines for the treatment of myocardial fibrosis Astragalus membranaceus(Fisch.),Lepidium apetalum Willd and Salvia miltiorrhiza Bge. Conclusion:Myocardial fibrosis is a complex pathological process,and the genes related to the imbalance of extracellular matrix synthesis and degradation and excessive deposition of collagen fibers play an important role in this process. This study provides a scientific reference for further exploring the pathogenesis of myocardial fibrosis,looking for therapeutic targets and potential therapeutic traditional Chinese medicines.