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Updated: Mar 27, 2026
Author Spotlight: Enhanced Murine AAA Model Using Elastase to Mimic Human Aneurysms
Published on: July 26, 2024
Screening and molecular functional analysis of telomere-related genes in abdominal aortic aneurysms based on
1Department of Vascular Surgery, Second Hospital of Hebei Medical University, Shijiazhuang, China.
Background:
Abdominal aortic aneurysm (AAA) is a life-threatening vascular condition characterized by progressive aortic dilation. However, 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:
We obtained the dataset GSE57691, including the RNA-expression data of AAA and normal control samples, from the GEO database. Weighted Gene Co-expression Network Analysis (WGCNA) was performed using the "WGCNA" package to identify AAA phenotype-related gene modules, and differential expression analysis of differentially expressed genes (DEGs) was conducted using the "limma" package. Biomarker identification was achieved through LASSO and Support Vector Machine (SVM) algorithms using the "glmnet" and "e1071" packages. GSEA_4.2.2 was utilized for gene enrichment analysis, and "CIBERSORT" and "estimate" were employed for 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 databases were utilized to construct the transcriptional regulatory network, and the "oncoPredict" package was employed to identify potential drugs. We verified the reliability of the model genes in vitro via the quantification assays (qPCR, western blot and ELISA) and the phenotypic determination assays (flow cytometry and trans-well).
Results:
Following WGCNA, AAA-related modules (MEmagenta/MEpink) were identified. Intersecting gene modules, DEGs, and telomere genes yielded eight candidates, among which KLF15 and ZBTB16 were prioritized via Lasso and SVM. Low expression of these biomarkers correlated with immune-inflammatory activation, whereas high expression was 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 analyzed telomere-related signatures in AAA and identified two crucial biomarkers linked to the immune infiltration of patients. Our findings furthered the understanding of telomere signatures in AAA progression.
Insights
This study identified KLF15 and ZBTB16 as key telomere-related biomarkers for abdominal aortic aneurysm (AAA). Their expression levels correlate with immune infiltration and disease progression, offering potential therapeutic targets for AAA.
Area of Science:
- Vascular Biology
- Genomics
- Immunology
Background:
- Abdominal aortic aneurysm (AAA) is a dangerous condition with no effective drug treatments.
- Understanding the molecular mechanisms of AAA progression is crucial for developing new therapies.
Purpose of the Study:
- To investigate telomere-related molecular signatures in AAA.
- To identify potential therapeutic targets for AAA by analyzing gene expression and immune infiltration.
Main Methods:
- Weighted Gene Co-expression Network Analysis (WGCNA) and differential gene expression analysis were performed on AAA and control samples.
- LASSO and Support Vector Machine (SVM) algorithms identified key biomarkers.
- Gene enrichment, immune infiltration, and single-cell RNA sequencing analyses were conducted.
- Transcriptional regulatory networks and potential drug targets were predicted, with in vitro validation.
Main Results:
- Two key biomarkers, KLF15 and ZBTB16, were identified, with expression levels correlating with immune infiltration and AAA progression.
- Low biomarker expression was linked to immune activation, while high expression indicated a suppressive microenvironment.
- Single-cell analysis revealed ZBTB16 enrichment in B cells, and Angiotensin II treatment downregulated both biomarkers in vascular cells.
- Overexpression of ZBTB16 demonstrated protective effects against Angiotensin II-induced damage.
Conclusions:
- Telomere-related signatures, specifically KLF15 and ZBTB16, are crucial in AAA pathogenesis and are linked to patient immune infiltration.
- These biomarkers offer insights into AAA progression and represent potential targets for novel pharmacotherapies.
