He Yunjun, Wang Xiaohui, Li Donglin, Zhu Qianqian, Xiang Yilang, He Yangyan, Zhang Hongkun
Department of the Vascular Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
J Thorac Dis. 2024 Apr 30;16(4):2510-2527. doi: 10.21037/jtd-24-370. Epub 2024 Apr 29.
Aortic aneurysm, characterized by abnormal dilation of the aorta, poses significant health risks. This study aims to investigate the interaction between 5-aminolevulinate synthase 2 () and GATA-binding protein 1 () in ferroptosis and oxidative stress responses in aortic aneurysm.
A weighted gene co-expression network analysis (WGCNA) was performed on the differentially expressed genes (DEGs) within the GSE9106 dataset to identify the key module. Subsequently, protein-protein interaction (PPI) network analysis was performed on the key module. Mouse aortic vascular smooth muscle cells (MOVAS) were treated with hydrogen peroxide (HO) to induce oxidative stress, and ferroptosis inducers and inhibitors were added to evaluate their effects on iron content and oxidative stress markers. Through a series of cellular experiments, we assessed cell viability, expression levels of GATA1 and iron mutation-associated proteins, as well as cellular phenotypes such as inflammatory responses and apoptosis rates.
Three candidate genes (, , and ) were upregulated in the thoracic aortic aneurysm (TAA) samples of the GSE9106 dataset. The HO treatment increased the MOVAS cells' iron content and oxidative stress, upregulated ALAS2 protein levels, and decreased the ferroptosis-related protein levels. overexpression reversed HO-induced apoptosis and increased the inflammatory cytokine levels. Additionally, the knockdown of partially reversed the protective mechanism of overexpressed on HO-induced ferroptosis.
overexpression reduced HO-induced oxidative damage and iron-induced apoptosis in MOVAS cells, and knockdown partially reversed this protective effect. These findings suggested that the and regulatory pathways may be potential therapeutic targets in aortic aneurysms.
主动脉瘤以主动脉异常扩张为特征，会带来重大健康风险。本研究旨在探讨5-氨基酮戊酸合酶2（ALAS2）与GATA结合蛋白1（GATA1）在主动脉瘤铁死亡和氧化应激反应中的相互作用。
对GSE9106数据集中的差异表达基因（DEGs）进行加权基因共表达网络分析（WGCNA）以识别关键模块。随后，对关键模块进行蛋白质-蛋白质相互作用（PPI）网络分析。用过氧化氢（H₂O₂）处理小鼠主动脉血管平滑肌细胞（MOVAS）以诱导氧化应激，并添加铁死亡诱导剂和抑制剂来评估它们对铁含量和氧化应激标志物的影响。通过一系列细胞实验，我们评估了细胞活力、GATA1和铁突变相关蛋白的表达水平，以及诸如炎症反应和凋亡率等细胞表型。
GSE9106数据集的胸主动脉瘤（TAA）样本中三个候选基因（ALAS2、GATA1和FTH1）上调。H₂O₂处理增加了MOVAS细胞的铁含量和氧化应激，上调了ALAS2蛋白水平，并降低了铁死亡相关蛋白水平。GATA1过表达逆转了H₂O₂诱导的凋亡并增加了炎症细胞因子水平。此外，敲低ALAS2部分逆转了过表达GATA1对H₂O₂诱导的铁死亡的保护机制。
GATA1过表达减少了H₂O₂诱导的MOVAS细胞氧化损伤和铁诱导的凋亡，敲低ALAS2部分逆转了这种保护作用。这些发现表明ALAS2和GATA1调控途径可能是主动脉瘤潜在的治疗靶点。
