Peng Zekun, Chen Hong, Wang Miao
State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
Clinical Pharmacology Center, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
Front Pharmacol. 2023 Jul 4;14:1211332. doi: 10.3389/fphar.2023.1211332. eCollection 2023.
Patients with anaphylaxis are at risk for ST-segment elevation myocardial infarction (STEMI). However, the pathological links between anaphylaxis and STEMI remain unclear. Here, we aimed to explore shared biological processes, immune effector cells, and hub genes of anaphylaxis and STEMI. Gene expression data for anaphylactic (GSE69063) and STEMI (GSE60993) patients with corresponding healthy controls were pooled from the Gene Expression Omnibus database. Differential expression analysis, enrichment analysis, and CIBERSORT were used to reveal transcriptomic signatures and immune infiltration profiles of anaphylaxis and STEMI, respectively. Based on common differentially expressed genes (DEGs), Gene Ontology analysis, cytoHubba algorithms, and correlation analyses were performed to identify biological processes, hub genes, and hub gene-related immune cells shared by anaphylaxis and STEMI. The robustness of hub genes was assessed in external anaphylactic (GSE47655) and STEMI (GSE61144) datasets. Furthermore, a murine model of anaphylaxis complicated STEMI was established to verify hub gene expressions. The logistic regression analysis was used to evaluate the diagnostic efficiency of hub genes. 265 anaphylaxis-related DEGs were identified, which were associated with immune-inflammatory responses. 237 STEMI-related DEGs were screened, which were involved in innate immune response and myeloid leukocyte activation. M0 macrophages and dendritic cells were markedly higher in both anaphylactic and STEMI samples compared with healthy controls, while CD4 naïve T cells and CD8 T cells were significantly lower. Enrichment analysis of 33 common DEGs illustrated shared biological processes of anaphylaxis and STEMI, including cytokine-mediated signaling pathway, response to reactive oxygen species, and positive regulation of defense response. Six hub genes were identified, and their expression levels were positively correlated with M0 macrophage abundance and negatively correlated with CD4 naïve T cell abundance. In external anaphylactic and STEMI samples, five hub genes (IL1R2, FOS, MMP9, DUSP1, CLEC4D) were confirmed to be markedly upregulated. Moreover, experimentally induced anaphylactic mice developed impaired heart function featuring STEMI and significantly increased expression of the five hub genes. DUSP1 and CLEC4D were screened as blood diagnostic biomarkers of anaphylaxis and STEMI based on the logistic regression analysis. Anaphylaxis and STEMI share the biological processes of inflammation and defense responses. Macrophages, dendritic cells, CD8 T cells, and CD4 naïve T cells constitute an immune cell population that acts in both anaphylaxis and STEMI. Hub genes (DUSP1 and CLEC4D) identified here provide candidate genes for diagnosis, prognosis, and therapeutic targeting of STEMI in anaphylactic patients.
过敏反应患者有发生ST段抬高型心肌梗死（STEMI）的风险。然而，过敏反应与STEMI之间的病理联系仍不清楚。在此，我们旨在探索过敏反应和STEMI共同的生物学过程、免疫效应细胞和枢纽基因。从基因表达综合数据库中汇集了过敏反应患者（GSE69063）和STEMI患者（GSE60993）以及相应健康对照的基因表达数据。分别使用差异表达分析、富集分析和CIBERSORT来揭示过敏反应和STEMI的转录组特征和免疫浸润谱。基于共同的差异表达基因（DEG），进行基因本体分析、cytoHubba算法和相关性分析，以识别过敏反应和STEMI共同的生物学过程、枢纽基因以及与枢纽基因相关的免疫细胞。在外部过敏反应数据集（GSE47655）和STEMI数据集（GSE61144）中评估枢纽基因的稳健性。此外，建立了过敏反应并发STEMI的小鼠模型以验证枢纽基因的表达。使用逻辑回归分析来评估枢纽基因的诊断效率。共鉴定出265个与过敏反应相关的DEG，它们与免疫炎症反应有关。筛选出237个与STEMI相关的DEG，它们参与先天免疫反应和髓系白细胞激活。与健康对照相比，过敏反应和STEMI样本中的M0巨噬细胞和树突状细胞均明显增多，而CD4初始T细胞和CD8 T细胞则显著减少。对33个共同DEG的富集分析表明了过敏反应和STEMI共同的生物学过程，包括细胞因子介导的信号通路、对活性氧的反应以及防御反应的正调控。鉴定出6个枢纽基因，它们的表达水平与M0巨噬细胞丰度呈正相关，与CD4初始T细胞丰度呈负相关。在外部过敏反应和STEMI样本中，证实5个枢纽基因（IL1R2、FOS、MMP9、DUSP1、CLEC4D）明显上调。此外，实验诱导的过敏反应小鼠出现了以STEMI为特征的心脏功能受损，且5个枢纽基因的表达显著增加。基于逻辑回归分析，筛选出DUSP1和CLEC4D作为过敏反应和STEMI的血液诊断生物标志物。过敏反应和STEMI共享炎症和防御反应的生物学过程。巨噬细胞、树突状细胞、CD8 T细胞和CD4初始T细胞构成了在过敏反应和STEMI中均起作用的免疫细胞群体。此处鉴定出的枢纽基因（DUSP1和CLEC4D）为过敏反应患者STEMI的诊断、预后和治疗靶点提供了候选基因。
