Zhang Shuli, Li Jiayin, Wang Ruichen, Zhao Xiaojie, Mei Zhu, Wang Xiaozeng
College of Medical and Bioinformatics Engineering, Northeastern University, Shenyang, China.
State Key Laboratory of Frigid Zone Cardiovascular Diseases, Cardiovascular Research Institute and Department of Cardiology, General Hospital of Northern Theater Command, Shenyang, China.
J Cell Mol Med. 2025 Jan;29(2):e70323. doi: 10.1111/jcmm.70323.
Abdominal aortic aneurysm (AAA) is the most prevalent dilated arterial aneurysm that poses a significant threat to older adults, but the molecular mechanisms linking senescence to AAA progression remain poorly understood. This study aims to identify cellular senescence-related genes (SRGs) implicated in AAA development and assess their potential as therapeutic targets. Four hundred and twenty-nine differentially expressed genes (DEGs) were identified from the GSE57691 training set, and 867 SRGs were obtained. Through the intersection of DEGs with SRGs, 19 differentially expressed senescence-related genes (DESRGs) were uncovered. Functional enrichment analysis was performed to explore their biological roles in AAA. To identify hub genes, we applied machine learning algorithms, including LASSO, SVM-RFE and random forest. These hub genes were then validated in two independent datasets. In the initial validation cohort, significant differences in the expression levels of BTG2, ETS1, ID1 and ITPR3 were observed between the AAA and control groups. Receiver operating characteristic (ROC) analysis demonstrated a robust diagnostic performance. Further validation across different AAA stages (small, large and ruptured AAA) identified ETS1 and ITPR3 as potential diagnostic genes. Subsequently, the diagnostic relevance of ETS1 and ITPR3 was further validated in human serum samples and mouse models of AAA. In addition, single-cell RNA sequencing suggests that senescent endothelial cells play a pivotal role in AAA progression, we further confirmed the correlation between ETS1 and ITPR3 and senescent endothelial cells by WB, IF and RT-qPCR. In conclusion, our study reveals the pivotal role of cellular senescence in AAA progression and identifies ETS1 and ITPR3 as promising diagnostic biomarkers.
腹主动脉瘤（AAA）是最常见的扩张性动脉动脉瘤，对老年人构成重大威胁，但衰老与AAA进展之间的分子机制仍知之甚少。本研究旨在鉴定与AAA发生相关的细胞衰老相关基因（SRGs），并评估它们作为治疗靶点的潜力。从GSE57691训练集中鉴定出429个差异表达基因（DEGs），并获得了867个SRGs。通过DEGs与SRGs的交集，发现了19个差异表达的衰老相关基因（DESRGs）。进行功能富集分析以探索它们在AAA中的生物学作用。为了鉴定枢纽基因，我们应用了机器学习算法，包括LASSO、支持向量机递归特征消除（SVM-RFE）和随机森林。然后在两个独立的数据集中对这些枢纽基因进行验证。在初始验证队列中，AAA组和对照组之间观察到BTG2、ETS1、ID1和ITPR3表达水平存在显著差异。受试者工作特征（ROC）分析显示出强大的诊断性能。对不同AAA阶段（小、大及破裂性AAA）的进一步验证确定ETS1和ITPR3为潜在的诊断基因。随后，在人血清样本和AAA小鼠模型中进一步验证了ETS1和ITPR3的诊断相关性。此外，单细胞RNA测序表明衰老内皮细胞在AAA进展中起关键作用，我们通过蛋白质免疫印迹（WB）、免疫荧光（IF）和逆转录定量聚合酶链反应（RT-qPCR）进一步证实了ETS1和ITPR3与衰老内皮细胞之间的相关性。总之，我们的研究揭示了细胞衰老在AAA进展中的关键作用，并确定ETS1和ITPR3为有前景的诊断生物标志物。
