摘要
目的 铁死亡在冠状病毒病2019(Coronavirus Disease 2019,COVID-19)相关的心血管疾病中起致病作用.本研究旨在鉴定严重急性呼吸综合征冠状病毒2型(severe acute respiratory syndrome coronavirus 2,SARS-CoV-2)感染引起的心肌损伤机制中潜在的铁死亡相关的关键基因.方法 对感染SARS-CoV-2的人诱导的多能干细胞源性心肌细胞(human induced pluripotent stem cell-derived cardiomyocytes,hiPSC-CMs)转录组数据进行生物信息学研究,包括铁死亡相关的差异表达基因(differentially expressed genes,DEGs)的鉴定、基因本体论(Gene Ontology,GO)和京都基因与基因组百科全书(Kyoto Encyclopedia of Genes and Genomes,KEGG)通路分析、蛋白质-蛋白质相互作用(protein-protein interactions,PPI)、关键基因鉴定以及转录因子-基因相互作用等,以探索铁死亡相关基因在COVID-19相关心肌损伤发病机制中的潜在作用.此外,针对关键基因的候选靶向药物进行了开发,为该疾病的诊疗提供理论依据.结果 通过比较感染或未感染SARS-CoV-2的hiPSC-CMs的转录谱数据,并与铁死亡数据库(FerrDb)基因取交集,筛选出80个铁死亡相关的DEGs.GO和KEGG通路富集分析表明,这些基因参与细胞对氧化应激和缺氧的反应、铁死亡、细胞坏死性凋亡、缺氧诱导因子1(hypoxia-inducible factor,HIF-1)信号通路、肿瘤坏死因子(Tumor Necrosis Factor,TNF)信号通路、白介素17(Interleukin 17,IL-17)信号通路、核因子-κB(Nuclear Factor-kappa B,NF-κB)信号通路等.使用PPI和cytoHubba鉴定的关键基因包括IL-6、JUN、PTGS2、TLR4、HIF1A、CAV1、HMOX1、SIRT1、EGFR和ATF3.转录因子RELA、NFKB1、EGR1、STAT3、JUN和SP1与大多数关键基因相互作用.筛选出针对关键基因的候选药物,包括去铁胺、氧气、辛伐他汀、乙酰半胱氨酸、姜黄素、醋酚酮、白藜芦醇、谷胱甘肽等.结论 分析感染SARS-CoV-2的hiPSC-CMs的转录谱数据,为理解SARS-CoV-2感染引起的心肌损伤的铁死亡相关病理机制的提供新视角.此外,探索铁死亡相关基因的候选靶向药物在未来对抗这种形式的心肌损伤方面具有巨大的潜力.
Abstract
Objective Ferroptosis plays a causative role in COVID-19-related cardiovascular disorders.The current study aimed to identify the potential ferroptosis-related key genes in the pathogenesis of myocardial damage caused by severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)infection.Methods Bioinformatics analyses of the transcriptional profiling of human induced pluripotent stem cell-derived cardiomyocytes(hiPSC-CMs)infected with SARS-CoV-2 were investigated,including ferroptosis-related differentially expressed genes(DEGs)identification,Gene Ontology(GO)and Kyoto Encyclopedia of Genes and Genomes(KEGG)pathway analyses,protein-protein interactions(PPI),hub genes identification,and TF-gene interactions to explore the potential roles of ferroptosis-related genes in the pathogenesis of COVID-19-related myocardial damage.Furthermore,exploitation of candidate drugs targeting hub genes was also explored to provide theoretical basis for its treatment.Results Eighty genes were identified as ferroptosis-related DEGs by comparing transcriptional profiling of hiPSC-CMs infected with or without SARS-CoV-2 and subsequent intersecting with FerrDb.GO and KEGG pathway enrichment analyses indicated that these ferroptosis-related genes involved in the cellular response to oxidative stress and hypoxia,ferroptosis,necroptosis,HIF-1 signaling pathway,TNF signaling pathway,IL-17 signaling pathway,NF-κB signaling pathway,and et al.Identified hub genes using PPIs and cytoHubba were IL-6,JUN,PTGS2,TLR4,HIF1A,CAV1,HMOX1,SIRT1,EGFR,and ATF3.TFs,namely RELA,NFKB1,EGR1,STAT3,JUN and SP1 interacted with most hub genes.Candidate drugs targeting hub genes were identified,namely deferoxamine,oxygen,simvastatin,N-Acetyl-L-cysteine,curcumin,acetovanillone,resveratrol,glutathione and et al.Conclusions Our comprehensive bioinformatics analyses of transcriptional profiling of hiPSC-CMs infected with SARS-CoV-2 provided us with a novel view of ferroptosis-related pathogenesis of myocardial damage caused by SARS-CoV-2 infection.Furthermore,exploitation of candidate drugs targeting ferroptois-related genes holds great promise in the future fight against this form of myocardial damage.
维普
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