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Analysis of Hub Genes and the Mechanism of Immune Infiltration in Stanford Type a Aortic Dissection.

ABSTRACT: Background: Stanford type A aortic dissection (AAD) is a catastrophic disease. An immune infiltrate has been found within the aortic wall of dissected aortic specimens. The recall and activation of macrophages are key events in the early phases of AAD. Herein, the immune filtration profile of AAD was uncovered. Methods: Gene expression data from the GSE52093, GSE98770 and GSE153434 datasets were downloaded from the Gene Expression Omnibus (GEO). The differentially expressed genes (DEGs) of each dataset were calculated and then integrated. A protein-protein interaction (PPI) network was established with the Search Tool for the Retrieval of Interacting Genes/Proteins (STRING), and the hub genes were identified in Cytoscape. Furthermore, gene ontology (GO) functional annotation and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis of hub genes were performed. Finally, we set GSE52093 and GSE98770 as the training set and GSE153434 as the validation set to assess immune infiltration in AAD using CIBERSORTx and analyzed the correlations between immune cells and hub genes in both the training and validation sets. Results: Sixty-one integrated DEGs were identified. The top 10 hub genes were selected from the PPI network, and 140 biological process (BP) terms and 12 pathways were enriched among the top 10 hub genes. The proportions of monocytes and macrophages were significantly higher in AAD tissues than in normal tissues. Notably, this result was consistent in the training set and the validation set. In addition, we found that among the hub genes, CA9, CXCL5, GDF15, VEGFA, CCL20, HMOX1, and SPP1 were positively correlated with CD14, a cell marker of monocytes, while CA9, CXCL5, GDF15, and VEGFA were positively correlated with CD68, a cell marker of macrophages in the training set. Finally, according to the results of the GO and KEGG analysis of hub genes, we found that the monocyte/macrophage-related genes were involved in immune-inflammatory responses through degradation of the extracellular matrix, endothelial cell apoptosis, hypoxia and the interaction of cytokines and chemokines. Conclusion: The monocyte-macrophage system plays a major role in immune-inflammatory responses in the development of AAD. Several hub genes are involved in this process via diverse mechanisms.

SUBMITTER: Gao H

PROVIDER: S-EPMC8284479 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundStanford type A aortic dissection (TAAD) is one of the most life-threatening cardiovascular emergencies with high mortality and morbidity, and necroptosis is a newly identified type of programmed cell death and contributes to the pathogenesis of various cardiovascular diseases. However, the role of necroptosis in TAAD has not been elucidated. This study was aimed at determining the role of necroptosis in TAAD using bioinformatics analyses.MethodsThe RNA sequencing dataset GSE153434 and the microarray dataset GSE52093 were obtained from Gene Expression Omnibus (GEO) database. Differentially expressed genes of necroptosis (NRDEGs) were identified based on differentially expressed genes (DEGs) and necroptosis gene set. Gene set enrichment analysis (GSEA) was applied to evaluate the gene enrichment signaling pathway in TAAD. The STRING database and Cytoscape software were used to establish and visualize protein-protein interaction (PPI) networks and identify the key functional modules of NRDEGs. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses of NRDEGs were also performed. Additionally, Spearman correlations were used to construct the necroptosis-related transcription factor-target genes regulatory network, immune infiltration patterns were analyzed using the ImmuCellAI algorithm, and the correlation between immune cell-type abundance and NRDEGs expression was investigated. The expression levels of NRDEGs and immune infiltration were additionally verified in the GSE52093 dataset.ResultsWe found that the necroptosis pathway was considerably enriched and activated in TAAD samples. Overall, 25 NRDEGs were identified including MLKL, RIPK1, and FADD, and among them, 18 were verified in the validation set. Moreover, GO and KEGG enrichment analyses found that NRDEGs were primarily involved in the tumor necrosis factor signaling pathway, nucleotide-binding oligomerization domain-like receptor signaling pathway, and interleukin-17 signaling pathway. The imbalance of Th17/Treg cells was identified in the TAAD samples. Furthermore, correlation analysis indicated that expression of NRDEGs was positively associated with proinflammatory immune-cell infiltrations and negatively associated with anti-inflammatory or regulatory immune-cell infiltrations.ConclusionsThe present findings suggest that necroptosis phenomenon exists in TAAD and correlates with immune cell infiltration, which indicate necroptosis may promote the development of TAAD through activating immune infiltration and immune response. This study paves a new road to future investigation of the pathogenic mechanisms and therapeutic strategies for TAAD.

Project description:Background: Stanford type A aortic dissection (ATAAD) is a common life-threatening event in the aorta. Recently, immune disorder has been linked to the risk factors that cause ATAAD at the molecular level. However, the specific immune-related gene signature during the progression is unclear. Methods: The GSE52093 and GSE98770 datasets related to ATAAD from the Gene Expression Omnibus (GEO) database were acquired. The immune gene expression levels were analyzed by single sample gene set enrichment analysis (ssGSEA). The correlations between gene networks and immune scores were determined by weighted gene correlation network analysis (WGCNA). The different immune subgroups were finally divided by consensus clustering. The differentially expressed genes (DEGs) were identified and subsequent functional enrichment analyses were conducted. The hub genes were identified by protein-protein interaction (PPI) network and functional similarities analyses. The immune cell infiltration proportion was determined by the CIBERSORT algorithm. Results: According to the ssGSEA results, the 13 ATAAD samples from the GEO database were divided into high- and low-immune subgroups according to the ssGSEA, WGCNA, and consensus clustering analysis results. Sixty-eight immune-related DEGs (IRDEGs) between the two subgroups were enriched in inflammatory-immune response biological processes, including leukocyte cell-cell adhesion, mononuclear cell migration, and myeloid leukocyte migration. Among these IRDEGs, 8 genes (CXCR4, LYN, CCL19, CCL3L3, SELL, F11R, DPP4, and VAV3) were identified as hub genes that represented immune-related signatures in ATAAD after the PPI and functional similarities analyses. The proportions of infiltrating CD8 T cells and M1 macrophages were significantly higher in ATAAD patients in the immune-high group than the immune-low group. Conclusion: Eight immune-related genes were identified as hub genes representing potential biomarkers and therapeutic targets linked to the immune response in ATAAD patients.

Project description:ObjectiveAcute aortic dissection is a life-threatening condition. Thoracic endovascular aortic repair (TEVAR), together with optimized medical treatment, is currently the first line treatment for acute Stanford type B aortic dissection. TEVAR can close the entry tear and reduce mortality. Aortic remodeling after TEVAR can directly affect the patient's long-term prognosis. The factors that influence aortic remodeling have, however, received insufficient clinical attention and remain unclear. It is very important to identify these factors.MethodsA total of 100 patients were continuously enrolled from 2011 to 2018 in 2 centers. Relevant data, including time from hospital admission to surgery, medicine use and aortic computed tomography angiography images obtained before and 6 months after surgery were collected. Patients were divided into favorable and adverse aortic remodeling groups, according to the degree of aortic remodeling. Analysis of variance and the chi-square test were performed using SPSS software to compare differences between groups and to determine the factors that influence postoperative aortic remodeling.ResultsThe proportion of single-stent implantations was higher in the favorable remodeling group than in the adverse remodeling group (79.5% vs. 53.8% in distal end of stent-graft level and 81.3% vs. 56.4% in diaphragm level, respectively, p < 0.05). The earlier the TEVAR procedure was performed, the better the aortic remodeling (3.4 days vs. 4.8 days in distal stent graft levels, and 3.6 days vs. 4.9 days in diaphragm level, respectively, p < 0.05), the presence of residual distal entry tears in the abdominal aorta also improved aortic remodeling after TEVAR (85.7% vs. 55.1% in the celiac trunk level, and 92.0% vs. 48.9% in the right renal artery level, respectively, p < 0.05).ConclusionSingle stent-graft implantation and early surgery were associated with favorable aortic remodeling. Distal entry tears were also conducive to aortic remodeling after surgery for aortic dissection.

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Analysis of Hub Genes and the Mechanism of Immune Infiltration in Stanford Type a Aortic Dissection.

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