Xu Jing, Yang Yuejin
State Key Laboratory of Cardiovascular Diseases, Fuwai Hospital & National Center for Cardiovascular Diseases, Beijing, China.
Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, China.
Ann Transl Med. 2023 Mar 15;11(5):189. doi: 10.21037/atm-22-3761. Epub 2023 Feb 24.
Atherosclerosis is an underlying cause of cardiovascular disease which is a leading cause of death worldwide. Foam cells play a crucial role in atherosclerotic lesion development, and macrophages and vascular smooth muscle cells (VSMCs) appear to contribute to the formation of the majority of atheromatous foam cells via oxidized low-density lipoprotein (ox-LDL) uptake.
An integrated, microarray-based analysis using GSE54666 and GSE68021, which contain samples of human macrophages and VSMCs incubated with ox-LDL, was conducted. The differentially expressed genes (DEGs) in each dataset were investigated via the linear models for microarray data () v. 3.40.6 software package in R v. 4.1.2 (The R Foundation for Statistical Computing). Gene ontology (GO) and pathway enrichment were performed via the ClueGO v. 2.5.8 and CluePedia v. 1.5.8 databases and the Database of Annotation, Visualization and Integrated (DAVID; https://david.ncifcrf.gov). The convergent DEGs in the two cell types were obtained, and the protein interactions and network of transcriptional factors were analyzed using the Search Tool for the Retrieval of Interacting Genes (STRING) v. 11.5 and the Transcriptional Regulatory Relationships Unraveled by Sentence-based Text-mining (TRRUST) v. 2 databases. The selected DEGs were further validated using external data from GSE9874, and a machine learning algorithm of the least absolute shrinkage and selection operator (LASSO) regression and receiver operating characteristic (ROC) analysis were applied to explore the candidate biomarkers.
We discovered the significant DEGs and pathways that were shared or unique among the 2 cell types, coupling with enriched lipid metabolism in macrophages, and upregulated defense response in VSMCs. Moreover, we identified , and as potential biomarkers and molecular targets for atherogenesis.
Our study provides a comprehensive summary of the landscape of the transcriptional regulations in macrophages and VSMCs under ox-LDL treatment from a bioinformatics perspective, which may contribute to a better understanding of the pathophysiological mechanisms of foam cell formation.
动脉粥样硬化是心血管疾病的潜在病因，而心血管疾病是全球主要的死亡原因。泡沫细胞在动脉粥样硬化病变发展中起关键作用，巨噬细胞和血管平滑肌细胞（VSMCs）似乎通过摄取氧化低密度脂蛋白（ox-LDL）促成了大多数动脉粥样硬化泡沫细胞的形成。
使用GSE54666和GSE68021进行了基于微阵列的综合分析，这两个数据集包含用ox-LDL孵育的人类巨噬细胞和VSMCs样本。通过R v. 4.1.2（R统计计算基金会）中的微阵列数据线性模型（limma）v. 3.40.6软件包研究每个数据集中的差异表达基因（DEGs）。通过ClueGO v. 2.5.8和CluePedia v. 1.5.8数据库以及注释、可视化和综合发现数据库（DAVID；https://david.ncifcrf.gov）进行基因本体（GO）和通路富集分析。获得两种细胞类型中的趋同DEGs，并使用基因相互作用检索搜索工具（STRING）v. 11.5和基于句子文本挖掘的转录调控关系解析（TRRUST）v. 2数据库分析蛋白质相互作用和转录因子网络。使用来自GSE9874的外部数据进一步验证所选的DEGs，并应用最小绝对收缩和选择算子（LASSO）回归和受试者工作特征（ROC）分析的机器学习算法来探索候选生物标志物。
我们发现了两种细胞类型中共享或独特的显著DEGs和通路，巨噬细胞中脂质代谢富集，VSMCs中防御反应上调。此外，我们确定了[具体基因名称未给出]作为动脉粥样硬化发生的潜在生物标志物和分子靶点。
我们的研究从生物信息学角度全面总结了ox-LDL处理下巨噬细胞和VSMCs中转录调控的情况，这可能有助于更好地理解泡沫细胞形成的病理生理机制。
