摘要： 目的 基于生物信息学分析心肌缺血/再灌注损伤（MI/RI）与坏死性凋亡共表达基因并验证。方法 基因表达图谱（GEO）数据库下载MI/RI表达谱数据（GSE67308和GSE19875），对GSE67308表达谱进行差异表达分析，筛选差异表达基因（DEGs）并进行基因集富分析和生物信号通路分析。对GSE67308表达谱数据进行免疫细胞浸润分析。利用分子标记数据库（MSigDB）和京都基因与基因组数据库（KEGG）检索坏死性凋亡相关基因，将DEGs与其交叉构建蛋白质-蛋白质相互作用（PPI）网络确定关键基因。通过单细胞测序分析平台分析关键基因在心脏各细胞类型中的表达情况，同时使用GSE19875数据集对关键基因表达进行验证。结果 共鉴定出1 054个DEGs，其中363个上调，691个下调。基因富集分析显示，DEGs功能主要与凋亡过程、免疫反应、细胞内信号转导调节相关；生物信号通路分析显示，DEGs主要参与TNF、NF-κB等信号通路的调控。免疫浸润分析结果表明，MI/RI心肌组织中自然杀伤细胞、单核细胞等免疫浸润程度高。PPI网络分析显示Il1b、TNF、Birc3、Ripk1是坏死性凋亡的关键基因。单细胞测序分析表明，白细胞中关键基因表达升高。GSE19875数据集中与对照组比较，MI/RI模型组中Il1b、TNF、Birc3、Ripk1表达显著升高（P < 0.01）。结论 MI/RI和参与调控坏死性凋亡的TNF信号通路、NF-κB信号通路高度相关；Il1b、TNF、Birc3、Ripk1是同时参与调节MI/RI和坏死性凋亡的关键基因；IL-1b、TNf、Birc3、Ripk1可能作为坏死性凋亡关键调节因子参与MI/RI过程。

基于生物信息学的心肌缺血/再灌注损伤与坏死性凋亡共表达基因分析

赵耀伟¹, 李宏玉², 马西元¹, 孟享泓¹, 唐强²

黑龙江中医药大学 1. 研究生院, 哈尔滨 150006;
2. 附属第二医院康复科, 哈尔滨 150001

收稿日期:2023-02-12出版日期:2024-01-30发布日期:2024-01-09
通讯作者:唐强E-mail:tangqiang1963@163.com
作者简介:赵耀伟(1994-),男,博士研究生.
基金资助:黑龙江省中医药管理局科研项目（ZHY2022-164）；黑龙江省博士后基金（LBH-Z20201）


关键词: 心肌缺血/再灌注损伤, 坏死性凋亡, 共表达基因, 生物信息学
Abstract: Objective To identify and validate co-expressed genes associated with myocardial ischemia/reperfusion injury (MI/RI) and necrotic apoptosis by bioinformatics analysis. Methods Gene expression profile data for MI/RI were obtained by GSE67308 and GSE19875 datasets from the Gene Expression Omnibus (GEO) database. Differential expression analysis was conducted on the GSE67308 dataset to identify differentially expressed genes (DEGs), followed by gene set enrichment analysis and biological pathway analysis. Moreover, immune cell infiltration analysis was performed on the GSE67308 dataset. Necrotic apoptosis-related genes were retrieved from the Molecular Signatures Database and the Kyoto Encyclopedia of Genes and Genomes (KEGG). A protein-protein interaction (PPI) network was constructed by overlapping DEGs with these necrotic apoptosis-related genes to identify key genes. Furthermore, the expression patterns of these key genes across various cardiac cell types were analyzed using a single-cell sequencing analysis platform, and validation of key gene expression was performed using the GSE19875 dataset. Results A total of 1 054 DEGs were identified, comprising 363 upregu-lated and 691 downregulated genes. Gene enrichment analysis revealed that DEGs were primarily associated with processes related to apoptosis, immune responses, and intracellular signaling regulation. Moreover, biological pathway analysis demonstrated that DEGs were predominantly involved in the regulation of signaling pathways such as tumor necrosis factor (TNF) and NF-κB. Immune infiltration analysis indicated a high degree of immune infiltration, particularly with natural killer cells and monocytes, in MI/RI myocardial tissue. PPI network analysis identified Il1b, TNF, Birc3, and Ripk1 as crucial genes in the context of necrotic apoptosis. Single-cell sequencing analysis showed the elevated expression of key genes within white blood cells. In comparison to the control group, the MI/RI model group in the GSE19875 dataset exhibited significantly increased expression of Il1b, TNF, Birc3, and Ripk1 (P < 0.01). Conclusion MI/RI is strongly correlated with the TNF signaling pathway and the NF-κB signaling pathway, both of which play pivotal roles in regulating necrotic apoptosis. Il1b, TNF, Birc3, and Ripk1 emerge as key genes that concurrently regulate both MI/RI and necrotic apoptosis. It is plausible that IL-1b, TNF, Birc3, and Ripk1 may serve as critical regulatory factors in the context of necrotic apoptosis during MI/RI.
Key words: myocardial ischemia/reperfusion injury, necrotic apoptosis, co-expressed gene, bioinformatics
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