Key ferroptosis-related genes in abdominal aortic aneurysm formation and rupture as determined by combining bioinformatics techniques

Abstract

ObjectivesAbdominal aortic aneurysm (AAA) is a cardiovascular disease with high mortality and pathogenesis closely related to various cell death types, e.g., autophagy, apoptosis and pyroptosis. However, the association between AAA and ferroptosis is unknown.MethodsGSE57691 and GSE98278 dataset were obtained from the Gene Expression Omnibus database, and a ferroptosis-related gene (FRG) set was downloaded from the FerrDb database. These data were normalized, and ferroptosis-related differentially expressed genes (FDEGs, AAA vs. normal samples) were identified using the limma package in R. FRGs expression was analyzed by Gene Set Expression Analysis (GSEA), and FDEGs were analyzed by Gene Ontology (GO) and Kyoto Encyclopedia of Genes (KEGG) pathway enrichment analyses using the clusterProfiler package in R and ClueGO in Cytoscape. Protein–protein interaction networks were assembled using Cytoscape, and crucial FDEGs were identified using CytoHubba. Critical FDEG transcription factors (TFs) were predicted with iRegulon. FDEGs were verified in GSE98278 set, and key FDEGs in AAA (compared with normal samples) and ruptured AAA (RAAA; compared with AAA samples) were identified. Ferroptosis-related immune cell infiltration and correlations with key genes were analyzed by CIBERSORT. Key FEDGs were reverified in Ang II-induced AAA models of ApoE–/– and CD57B/6J mice by immunofluorescence assay.ResultsIn AAA and normal samples, 40 FDEGs were identified, and the expression of suppressive FRGs was significantly downregulated with GSEA. For FDEGs, the GO terms were response to oxidative stress and cellular response to external stimulus, and the KEGG pathways were the TNF and NOD-like receptor signaling pathways. IL6, ALB, CAV1, PTGS2, NOX4, PRDX6, GPX4, HSPA5, HSPB1, and NCF2 were the most enriched genes in the crucial gene cluster. CEBPG, NFAT5, SOX10, GTF2IRD1, STAT1, and RELA were potential TFs affecting these crucial genes. Ferroptosis-related immune cells involved in AAA formation were CD8+ T, naive CD4+ T, and regulatory T cells (Tregs); M0 and M2 macrophages; and eosinophils. Tregs were also involved in RAAA. GPX4, SLC2A1, and PEBP1 expression was downregulated in both the RAAA and AAA samples. GPX4 and PEBP1 were more important in AAA because they influenced ferroptosis-related immune cell infiltration, and SLC2A1 was more important in RAAA.ConclusionsThis is the first study to show that ferroptosis is crucial to AAA/RAAA formation. The TNF and NOD-like signaling pathways and ferroptosis-related immune cell infiltration play key roles in AAA/RAAA. GPX4 is a key ferroptosis-related gene in AAA. Ferroptosis and related genes might be promising targets in the treatment of AAA/RAAA.

Ferrostatin‐1 inhibits ferroptosis of vascular smooth muscle cells and alleviates abdominal aortic aneurysm formation through activating the SLC7A11/GPX4 axis

“…Previous data have indicated that iron ion levels are elevated in arterial tissue in AAA, and that the process of AAA is exacerbated by oxidative stress and inflammatory responses due to iron overload 22 . In a recently published article, SLC7A11 and GPX4 gene expressions were shown to be expressed in diseased vascular tissue and normal tissue in patients with AAA and showed some correlation with tissue infiltrating immune cells 9 . In addition, it has been reported that abnormal expression of SLC7A11/GPX4 genes in locally infiltrating macrophages in the development of AAA leads to an oxidative imbalance and enhanced migration of macrophages, which promotes the progression of AAA 23 .…”

“…22 In a recently published article, SLC7A11 and GPX4 gene expressions were shown to be expressed in diseased vascular tissue and normal tissue in patients with AAA and showed some correlation with tissue infiltrating immune cells. 9 In addition, it has been reported that abnormal expression of SLC7A11/GPX4 genes in locally infiltrating macrophages in the development of AAA leads to an oxidative imbalance and enhanced migration of macrophages, which promotes the progression of AAA. 23 Previous studies have found that AngII plays an important role in the initiation, formation, and rupture of AAA, which may be related to macrophage infiltration.…”

“…Ferroptosis has been reported to be associated with the development of AAA, and RvD1 may ameliorate AAA by mediating the process of ferroptosis in macrophages through FPR2 8 . Another study found that ferroptosis‐related immune cell infiltration plays an important role in the development of AAA 9 …”

“…8 Another study found that ferroptosis-related immune cell infiltration plays an important role in the development of AAA. 9 The SLC7A11/GPX4 signaling pathway is mainly involved in the regulation of various injury-related biological processes, such as ischemia-reperfusion injury in brain and heart and lung injury, by inhibiting ferroptosis in cells. [10][11][12] It has also been reported that the SLC7A11/ GPX4 signaling pathway is also involved in the development of cognitive impairment after cerebral ischemia.…”

Structural characterization of a sulfated polysaccharide from Gracilariopsis lemaneiformis and its potentiation of cisplatin antitumor activity in Colon-26 carcinoma tumor-bearing mice by inducing ferroptosis

“…GP90 activated the innate immune response in combination with CP, and also involved the NOD-like receptor signalling pathway, Toll-like receptor signalling pathway, and T cell receptor signalling pathway, and plays a role in ferroptosis by regulating oxidative stress. 46 Further study will address the effect of GP90 on the immune function in CP-treated C26 carcinoma tumor-bearing mice.…”