Abstract
The molecular mechanism of AAA formation is still poorly understood and has not been fully elucidated. The study was designed to identify the immune-related genes, immune-RAS in AAA using bioinformatics methods. The GSE175683 datasets were downloaded from the GEO database. The DEseq2 software was used to identify differentially expressed genes (DEGs). SUVA pipeline was used to quantify AS events and RAS events. KOBAS 2.0 server was used to identify GO terms and KEGG pathways to sort out functional categories of DEGs. The CIBERSORT algorithm was used with the default parameter for estimating immune cell fractions. Nine samples from GSE175683 were used to construct the co-disturbed network between expression of SFs and splicing ratio of RAS events. PCA analysis was performed by R package factoextra to show the clustering of samples, and the pheatmap package in R was used to perform the clustering based on Euclidean distance. The results showed that there were 3,541 genes significantly differentially expressed, of which 177 immune-related genes were upregulated and 48 immune-related genes were downregulated between the WT and WTA group. Immune-RAS events were mainly alt5P and IR events, and about 60% of it was complex splicing events in AAA. The WT group and the WTA group can be clearly distinguished in the first principal component by using the splicing ratio of immune-RAS events. Two downregulated genes, Nr4a1 and Nr4a2, and eight upregulated genes, Adipor2, Akt2, Bcl3, Dhx58, Pparg, Ptgds, Sytl1, and Vegfa were identified among the immune-related genes with RAS and DEGs. Eighteen differentially expressed SFs were identified and displayed by heatmap. The proportion of different types of cells and ratio of the average ratio of different cells were quite different. Both M1 and M2 types of macrophages and plasma cells were upregulated, while M0 type was downregulated in AAA. The proportion of plasma cells in the WTA group had sharply increased. There is a correlation between SF expression and immune cells/immune-RAS. Sf3b1, a splicing factor with significantly different expression, was selected to bind on a mass of immune-related genes. In conclusion, our results showed that immune-related genes, immune-RAS, and SFs by genome-wide identification were involved in AAA.
Highlights
Abdominal aortic aneurysm (AAA) refers to the permanent and localized expansion of the abdominal aortic wall exceeding 50% of the normal vascular diameter, and is usually diagnosed when the abdominal aorta is more than 3 cm in diameter (Chaikof et al, 2018; Cai et al, 2021)
Based on the RNAseq data of GSE175683, we explored the genome-wide identification of immune-regulated alternative splicing events (RAS) and splicing regulators involved in AAA
We further focused on the Alternative splicing (AS) of immune genes and used software SUVA to analyze and identify immune-RAS events
Summary
Abdominal aortic aneurysm (AAA) refers to the permanent and localized expansion of the abdominal aortic wall exceeding 50% of the normal vascular diameter, and is usually diagnosed when the abdominal aorta is more than 3 cm in diameter (Chaikof et al, 2018; Cai et al, 2021). AAA is a fatal vascular disease in human, which is a chronic degenerative disease of abdominal aorta In this process, the inflammatory responses and immune system work effectively through the attraction of inflammatory cells, the secretion of proinflammatory factors, and the subsequent upregulation of MMP (Li et al, 2018). Increased knowledge indicates that the immune process is involved in the pathogenesis of AAA (Jagadesham et al, 2008; Liu et al, 2015) Some immune cells such as macrophages, CD4+ T cells, and B cells play an important role in the diseased aortic wall through phenotypic regulation (Maiellaro and Taylor, 2007; Schaheen et al, 2016). The current understanding may provide new insights into the role of inflammation and immune response in AAA. We will discuss immune-related genes and its regulation of AS, and provide new mechanism insights for the development of immune-targeted therapy in AAA
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