Integrated Analysis and Validation of Ferroptosis-related Genes and Immune Infiltration in Acute Myocardial Infarction

Overview

Journal BMC Cardiovasc Disord

Publisher Biomed Central

Specialty Cardiology & Vascular Diseases

Date 2024 Feb 24

PMID 38402377

Authors

Xinyu Wu

Jingru Li

Shengjie Chai

Chaguo Li

Si Lu

Suli Bao

Shuai Yu

Hao Guo

Jie He

Yunzhu Peng

Huang Sun

Luqiao Wang

Affiliations

Soon will be listed here.

Abstract

Background: Acute myocardial infarction (AMI) is indeed a significant cause of mortality and morbidity in individuals with coronary heart disease. Ferroptosis, an iron-dependent cell death, is characterized by the accumulation of intracellular lipid peroxides, which is implicated in cardiomyocyte injury. This study aims to identify biomarkers that are indicative of ferroptosis in the context of AMI, and to examine their potential roles in immune infiltration.

Methods: Firstly, the GSE59867 dataset was used to identify differentially expressed ferroptosis-related genes (DE-FRGs) in AMI. We then performed gene ontology (GO) and functional enrichment analysis on these DE-FRGs. Secondly, we analyzed the GSE76591 dataset and used bioinformatic methods to build ceRNA networks. Thirdly, we identified hub genes in protein-protein interaction (PPI) network. After obtaining the key DE-FRGs through the junction of hub genes with ceRNA and least absolute shrinkage and selection operator (LASSO). ImmucellAI was applied to estimate the immune cell infiltration in each sample and examine the relationship between key DE-FRGs and 24 immunocyte subsets. The diagnostic performance of these genes was further evaluated using the receiver operating characteristic (ROC) curve analysis. Ultimately, we identified an immune-related ceRNA regulatory axis linked to ferroptosis in AMI.

Results: Among 56 DE-FRGs identified in AMI, 41 of them were integrated into the construction of competitive endogenous RNA (ceRNA) networks. TLR4 and PIK3CA were identified as key DE-FRGs and PIK3CA was confirmed as a diagnostic biomarker for AMI. Moreover, CD4_native cells, nTreg cells, Th2 cells, Th17 cells, central-memory cells, effector-memory cells, and CD8_T cells had higher infiltrates in AMI samples compared to control samples. In contrast, exhausted cells, iTreg cells, and Tfh cells had lower infiltrates in AMI samples. Spearman analysis confirmed the correlation between 24 immune cells and PIK3CA/TLR4. Ultimately, we constructed an immune-related regulatory axis involving XIST and OIP5-AS1/miR-216a/PIK3CA.

Conclusion: Our comprehensive analysis has identified PIK3CA as a robust and promising biomarker for this condition. Moreover, we have also identified an immune-related regulatory axis involving XIST and OIP5-AS1/miR-216a/PIK3CA, which may play a key role in regulating ferroptosis during AMI progression.

References

Li J, Sun G, Ma H, Wu X, Li C, Ding P . Identification of immune-related hub genes and miRNA-mRNA pairs involved in immune infiltration in human septic cardiomyopathy by bioinformatics analysis. Front Cardiovasc Med. 2022; 9:971543. PMC: 9530044. DOI: 10.3389/fcvm.2022.971543. View

Zhang S, Li Y, Xin S, Yang L, Jiang M, Xin Y . Insight into LncRNA- and CircRNA-Mediated CeRNAs: Regulatory Network and Implications in Nasopharyngeal Carcinoma-A Narrative Literature Review. Cancers (Basel). 2022; 14(19). PMC: 9559536. DOI: 10.3390/cancers14194564. View

Tong Z, Li G, Su C, Zhou L, Zhang L, Chen Q . L-Borneol 7-O-[-D-Apiofuranosyl-(1→6)]--D-Glucopyranoside Alleviates Myocardial Ischemia-Reperfusion Injury in Rats and Hypoxic/Reoxygenated Injured Myocardial Cells via Regulating the PI3K/AKT/mTOR Signaling Pathway. J Immunol Res. 2022; 2022:5758303. PMC: 9119761. DOI: 10.1155/2022/5758303. View

Barrera M, Aguilera S, Castro I, Carvajal P, Jara D, Molina C . Dysfunctional mitochondria as critical players in the inflammation of autoimmune diseases: Potential role in Sjögren's syndrome. Autoimmun Rev. 2021; 20(8):102867. DOI: 10.1016/j.autrev.2021.102867. View

Kanehisa M, Goto S . KEGG: kyoto encyclopedia of genes and genomes. Nucleic Acids Res. 1999; 28(1):27-30. PMC: 102409. DOI: 10.1093/nar/28.1.27. View

Liang J, Wang D, Lin H, Chen X, Yang H, Zheng Y . A Novel Ferroptosis-related Gene Signature for Overall Survival Prediction in Patients with Hepatocellular Carcinoma. Int J Biol Sci. 2020; 16(13):2430-2441. PMC: 7378635. DOI: 10.7150/ijbs.45050. View

Tam C, Tse H . Antiplatelet Therapy Aims and Strategies in Asian Patients with Acute Coronary Syndrome or Stable Coronary Artery Disease. J Clin Med. 2022; 11(24). PMC: 9784545. DOI: 10.3390/jcm11247440. View

Zhou D, Liu X, Wang X, Yan F, Wang P, Yan H . A prognostic nomogram based on LASSO Cox regression in patients with alpha-fetoprotein-negative hepatocellular carcinoma following non-surgical therapy. BMC Cancer. 2021; 21(1):246. PMC: 7938545. DOI: 10.1186/s12885-021-07916-3. View

Wu X, Li Y, Zhang S, Zhou X . Ferroptosis as a novel therapeutic target for cardiovascular disease. Theranostics. 2021; 11(7):3052-3059. PMC: 7847684. DOI: 10.7150/thno.54113. View

10.

Li H, Ge Y, Fei G, Wang Z, Wang S, Wei P . Development and validation of a combined ferroptosis and immune prognostic signature for lung adenocarcinoma. Transl Cancer Res. 2022; 11(10):3620-3633. PMC: 9641098. DOI: 10.21037/tcr-22-992. View

11.

Li J, Wu X, Ma H, Sun G, Ding P, Lu S . New developments in non-exosomal and exosomal ncRNAs in coronary artery disease. Epigenomics. 2022; 14(21):1355-1372. DOI: 10.2217/epi-2022-0201. View

12.

Wang D, Li X, Jiao D, Cai Y, Qian L, Shen Y . LCN2 secreted by tissue-infiltrating neutrophils induces the ferroptosis and wasting of adipose and muscle tissues in lung cancer cachexia. J Hematol Oncol. 2023; 16(1):30. PMC: 10044814. DOI: 10.1186/s13045-023-01429-1. View

13.

Chin C, Chen S, Wu H, Ho C, Ko M, Lin C . cytoHubba: identifying hub objects and sub-networks from complex interactome. BMC Syst Biol. 2014; 8 Suppl 4:S11. PMC: 4290687. DOI: 10.1186/1752-0509-8-S4-S11. View

14.

Wang J, Zhuo Z, Wang Y, Yang S, Chen J, Wang Y . Identification and Validation of a Prognostic Risk-Scoring Model Based on Ferroptosis-Associated Cluster in Acute Myeloid Leukemia. Front Cell Dev Biol. 2022; 9:800267. PMC: 8814441. DOI: 10.3389/fcell.2021.800267. View

15.

Chen X, Kang R, Kroemer G, Tang D . Ferroptosis in infection, inflammation, and immunity. J Exp Med. 2021; 218(6). PMC: 8126980. DOI: 10.1084/jem.20210518. View

16.

Li H, Yang H, Wang D, Zhang L, Ma T . Peroxiredoxin2 (Prdx2) Reduces Oxidative Stress and Apoptosis of Myocardial Cells Induced by Acute Myocardial Infarction by Inhibiting the TLR4/Nuclear Factor kappa B (NF-κB) Signaling Pathway. Med Sci Monit. 2020; 26:e926281. PMC: 7722772. DOI: 10.12659/MSM.926281. View

17.

Le T, Aronow R, Kirshtein A, Shahriyari L . A review of digital cytometry methods: estimating the relative abundance of cell types in a bulk of cells. Brief Bioinform. 2020; 22(4). PMC: 8293826. DOI: 10.1093/bib/bbaa219. View

18.

Mou Y, Wang J, Wu J, He D, Zhang C, Duan C . Ferroptosis, a new form of cell death: opportunities and challenges in cancer. J Hematol Oncol. 2019; 12(1):34. PMC: 6441206. DOI: 10.1186/s13045-019-0720-y. View

19.

Yu G, Wang L, Han Y, He Q . clusterProfiler: an R package for comparing biological themes among gene clusters. OMICS. 2012; 16(5):284-7. PMC: 3339379. DOI: 10.1089/omi.2011.0118. View

20.

Peet C, Ivetic A, Bromage D, Shah A . Cardiac monocytes and macrophages after myocardial infarction. Cardiovasc Res. 2019; 116(6):1101-1112. PMC: 7177720. DOI: 10.1093/cvr/cvz336. View