神经前体细胞发育性下调基因9（NEDD9）的过表达可减少氧化型低密度脂蛋白（ox-LDL）诱导的动脉粥样硬化血管内皮细胞失巢凋亡。
Overexpression of Neural Precursor Cell Expressed Developmentally Downregulated 9 (NEDD9) reduces ox-LDL-induced Anoikis in atherosclerotic vascular endothelial cells.
作者信息
Zhou Xiaowei, Hu Qinghua, Yu Meihong, Li Kaixuan
机构信息
Department of Cardiovascular Surgery, Xiangya Hospital, Central South University, Changsha 410008, PR China.
National Clinical Research Center for Geriatric Disorders,Xiangya Hospital, Central South University, Changsha, Hunan 410008, PR China.
出版信息
Int J Cardiol Heart Vasc. 2025 Jan 17;56:101609. doi: 10.1016/j.ijcha.2025.101609. eCollection 2025 Feb.
OBJECTIVE
This study purposes to explore the action of the Anoikis gene in vascular endothelial cell injury, explore diagnostic biomarkers, and provide new insights into potential molecular mechanisms, as well as offer a new perspective for disease detection and treatment.
METHODS
The Anoikis gene set was used for enrichment analysis on the Gene Expression Omnibus (GEO: GSE100927) dataset, to identify the intersection genes related to Atherosclerosis. Further, the expression and pathway enrichment of Anoikis genes in GSE100927 was investigated. The Least Absolute Shrinkage and Selection Operator (LASSO) method for dimensionality reduction modeling was employed to obtain Atherosclerosis-related genes and construct Anoikis score. The NEDD9, FOSB, and ERCC1 expression in ox-LDL-induced the Bend.3 cells was validated by reverse transcription quantitative polymerase chain reaction (RT-qPCR). Overexpression or silencing NEDD9 on Anoikis in ox-LDL and detachment-induced the Bend.3 cells was analyzed by using Cell Counting Kit-8 (CCK8), 5-Ethynyl-2'-deoxyuridine (EdU), and flow cytometry assays.
RESULTS
Based on Anoikis gene analysis, NFIL3, NR4A3, ADAMTS4, NEDD9, STX17-AS1, and CSF3 were found to be under-expressed, while FOSB and ERCC1 were found to be over-expressed in the atherosclerosis group compared to the normal group. LASSO regression analysis yielded an Anoikis score = -9.522 × NFIL3 - 3.410 × NEDD9 + 2.728 × ADAMTS4 + 1.178 × FOSB + 5.896 × ERCC1 + 1.558. Compared with the blank group, NEDD9, FOSB, and ERCC1 were under-expressed in the ox-LDL intervention group. si-NEDD9 promoted an increase in reactive oxygen species (ROS) and apoptosis levels in the Bend.3 cells intervened by ox-LDL. Transfection with oe-NEDD9 increased the viability of Bend.3 cells induced by the ox-LDL and detachment, while decreasing ROS and apoptosis levels.
CONCLUSION
This study developed a reliable atherosclerotic Anoikis model for predicting endothelial cell injury. During Anoikis genes, the overexpression of NEDD9 reduces ox-LDL and detachment-induced endothelial cell Anoikis.
目的
本研究旨在探讨失巢凋亡基因在血管内皮细胞损伤中的作用，探索诊断生物标志物，为潜在的分子机制提供新见解，并为疾病检测和治疗提供新视角。
方法
利用失巢凋亡基因集对基因表达综合数据库（GEO：GSE100927）数据集进行富集分析，以鉴定与动脉粥样硬化相关的交集基因。此外，研究了GSE100927中失巢凋亡基因的表达及通路富集情况。采用最小绝对收缩和选择算子（LASSO）降维建模方法获得动脉粥样硬化相关基因并构建失巢凋亡评分。通过逆转录定量聚合酶链反应（RT-qPCR）验证氧化型低密度脂蛋白（ox-LDL）诱导的Bend.3细胞中NEDD9、FOSB和ERCC1的表达。使用细胞计数试剂盒-8（CCK8）、5-乙炔基-2'-脱氧尿苷（EdU）和流式细胞术分析，对ox-LDL和脱离诱导的Bend.3细胞中NEDD9在失巢凋亡方面的过表达或沉默情况进行分析。
结果
基于失巢凋亡基因分析，发现与正常组相比，动脉粥样硬化组中NFIL3、NR4A3、ADAMTS4、NEDD9、STX17-AS1和CSF3表达下调，而FOSB和ERCC1表达上调。LASSO回归分析得出失巢凋亡评分= -9.522×NFIL3 - 3.410×NEDD9 + 2.728×ADAMTS4 + 1.178×FOSB + 5.896×ERCC1 + 1.558。与空白组相比，ox-LDL干预组中NEDD9、FOSB和ERCC1表达下调。si-NEDD9促进了ox-LDL干预的Bend.3细胞中活性氧（ROS）水平和凋亡水平的升高。用oe-NEDD9转染可提高ox-LDL和脱离诱导的Bend.3细胞的活力，同时降低ROS水平和凋亡水平。
结论
本研究建立了一种可靠的用于预测内皮细胞损伤的动脉粥样硬化失巢凋亡模型。在失巢凋亡基因中，NEDD9的过表达可减少ox-LDL和脱离诱导的内皮细胞失巢凋亡。
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