Screening and molecular function of telomere related genes in abdominal aortic aneurysms based on bioinformatics

Abstract

Background: Abdominal aortic aneurysm (AAA) is a life-threatening vascular condition characterized by progressive aortic dilation, yet no effective pharmacotherapies exist to halt its progression. This study aimed to investigate telomere-related molecular signatures in AAA to identify potential targets for therapeutic development. Method: The dataset GSE57691 including the RNA-expression data of AAA and normal control samples were derived from GEO database. Weighted Gene Co-expression Network Analysis (WGCNA) for AAA phenotype-related gene module was conducted by “WGCNA” package, the differential expression analysis for differentially expressed genes (DEGs) was conducted by the “limma” package. The LASSO and Support Vector Machines (SVM) algorithm for the biomarker identifying were performed by using the “glmnet” and “e1071” package, GSEA_4.2.2 was utilized for gene enrichment analysis, and “CIBERSORT” and “estimate” package was employed for the immune infiltration. An independent single-cell RNA-seq dataset (GSE237230) was analyzed using the Seurat pipeline to characterize the cellular landscape and validate biomarker expression at single-cell resolution. Finally, the hTFtarget and Encori for transcriptional regulatory network and “oncoPredict” package for potential drugs were performed, and we verified the reliability of the model genes in vitro via qPCR, western blot and trans-well assay. Results: Following WGCNA, AAA-related modules (MEmagenta/MEpink) were identified. Intersecting gene modules, DEGs, and telomere genes yielded 8 candidates, from which KLF15 and ZBTB16 were prioritized via Lasso and SVM. Low expression of these biomarkers correlated with immune-inflammatory activation, whereas high expression linked to a suppressive microenvironment that alleviated AAA progression. Furthermore, a transcriptional regulatory network was constructed, identifying key target mRNAs and potential drugs. Single-cell analysis confirmed distinct clusters and specific enrichment of ZBTB16 in B cells. Angiotensin II (Ang II) treatment downregulated KLF15 and ZBTB16 in T/G HA-VSMCs. Overexpression of ZBTB16 attenuated Ang II-induced inflammation, apoptosis, and migration, and suppressed MMP-2/9 levels, indicating inhibited migratory activity. Conclusion: We explored the telomere-related signatures in AAA and identified two crucial biomarkers indicating the immune infiltration of patients. Our findings promoted the understanding of telomere signature in AAA progression.