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心脏移植后心肌缺血/再灌注中铁死亡相关枢纽基因及免疫浸润的生物信息学分析

Bioinformatics analysis of ferroptosis-related hub genes and immunoinfiltration in myocardial ischemia/reperfusion following heart transplantation.

作者信息

Zhang Yuxi, Tang Qiao, Cui Jiahui, Li Yanan, Xu Heng, Qiu Zhen, Lei Shaoqing, Xue Rui, Sun Qian, Xia Zhongyuan

机构信息

Department of Anesthesiology, Renmin Hospital of Wuhan University, 238 Jiefang Road, Wuchang District, Wuhan, 430061, China.

Department of Anesthesiology, Renmin Hospital, Hubei University of Medicine, Shiyan, 442000, China.

出版信息

BMC Cardiovasc Disord. 2025 Jan 10;25(1):16. doi: 10.1186/s12872-024-04462-1.

DOI:10.1186/s12872-024-04462-1
PMID:39794696
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11724544/
Abstract

BACKGROUND

Ischemia/reperfusion (I/R) is an inevitable pathophysiological process during heart transplantation, and ferroptosis is an important pathogenic mechanism. Unlike other modes of cell death, ferroptosis depends on the accumulation of iron within the cell and the oxidative degradation of polyunsaturated fatty acids. Dysregulation of this pathway has been linked to the progression of multiple pathological conditions, making it an attractive target for therapeutic intervention. Therefore, this study aims to explore the effect of ferroptosis on I/R during heart transplantation.

METHODS

GEO2R was applied to identify differentially expressed genes (DEGs) obtained from GSE50884 data, which was involved in I/R and heart transplantation. And ferroptosis-related DEGs (FRDEGs) were screened by venn diagram with ferroptosis-related genes downloaded from FerDb database. FRDEGs was enriched and analyzed by GO and KEGG, and hub genes related to ferroptosis were screened by Cytoscape software and database STRING. Additionally, considering the relationship between ferroptosis and immunity, CIBERSORTx was to analyze the infiltration of 22 kinds of immune cells in I/R during heart transplantation, and the correlation between each immune cell and the expression of FRDEGs was also discussed. Finally, the mouse model of heart transplantation with I/R was constructed, and the hub genes was verified by RT-qPCR and western blot.

RESULTS

12 FRDEGs were identified out of 327 DEGs in GSE50844, which were mainly involved in ferroptosis and other pathways. Three hub genes (SLC7A11, PSAT1, ASNS) were obtained by the degree algorithm of cytohubba plug-in. Immunoinfiltration analysis showed that 16 of 22 immune cells changed, and the immune score of heart transplantation with I/R was higher than that without I/R. In addition, hub genes exhibited significant correlation with Eosinophils, NK cells resting, Dendritic cells resting, NK cells activated and T cells CD4 memory activated. We verified the expression of SLC7A11, PSAT1 and ASNS was higher than that in normal tissues using RT-qPCR and western blot in mouse models of heart transplantation with I/R, companied by ferroptosis aggravated is involved.

CONCLUSIONS

In short, ferroptosis is involved in I/R injury during heart transplantation, which is related to immune cell infiltration. Three hub genes (SLC7A11, PSAT1 and ASNS) identified in this study provide therapeutic targets for ameliorating I/R injury in heart transplantation.

摘要

背景

缺血/再灌注（I/R）是心脏移植过程中不可避免的病理生理过程，铁死亡是其重要的致病机制。与其他细胞死亡模式不同，铁死亡依赖于细胞内铁的积累和多不饱和脂肪酸的氧化降解。该通路的失调与多种病理状况的进展有关，使其成为治疗干预的一个有吸引力的靶点。因此，本研究旨在探讨铁死亡在心脏移植I/R过程中的作用。

方法

应用GEO2R识别从GSE50884数据中获得的差异表达基因（DEGs），该数据涉及I/R和心脏移植。通过与从FerDb数据库下载的铁死亡相关基因绘制韦恩图筛选铁死亡相关DEGs（FRDEGs）。利用GO和KEGG对FRDEGs进行富集和分析，并通过Cytoscape软件和STRING数据库筛选与铁死亡相关的枢纽基因。此外，考虑到铁死亡与免疫的关系，采用CIBERSORTx分析心脏移植I/R过程中22种免疫细胞的浸润情况，并探讨每种免疫细胞与FRDEGs表达之间的相关性。最后，构建心脏移植I/R小鼠模型，通过RT-qPCR和western blot验证枢纽基因。

结果

在GSE50844的327个DEGs中鉴定出12个FRDEGs，主要参与铁死亡和其他通路。通过cytohubba插件的度算法获得了3个枢纽基因（SLC7A11、PSAT1、ASNS）。免疫浸润分析显示，22种免疫细胞中有16种发生变化，心脏移植I/R组的免疫评分高于非I/R组。此外，枢纽基因与嗜酸性粒细胞、静息NK细胞、静息树突状细胞、活化NK细胞和CD4记忆活化T细胞呈显著相关。在心脏移植I/R小鼠模型中，我们用RT-qPCR和western blot验证了SLC7A11、PSAT1和ASNS的表达高于正常组织，同时伴有铁死亡加剧。

结论

简而言之，铁死亡参与了心脏移植过程中的I/R损伤，这与免疫细胞浸润有关。本研究鉴定出的3个枢纽基因（SLC7A11、PSAT1和ASNS）为改善心脏移植I/R损伤提供了治疗靶点。

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