Zhu Guoqi, Gao Yanhua, Qian Jun, Lai Yan, Lin Hao, Liu Chengxing, Chen Fei, Liu Xuebo
Department of Cardiology, Tongji Hospital, Tongji University School of Medicine, Shanghai, China.
Front Cardiovasc Med. 2023 Mar 28;10:951242. doi: 10.3389/fcvm.2023.951242. eCollection 2023.
Plaque rupture and acute atherothrombosis, resulting from continued progression of atherosclerotic plaques (APs), are major contributors to acute clinical events such as stroke or myocardial infarction. This article aimed to explore the gene signatures and potential molecular mechanisms in the progression and instability of APs and to identify novel biomarkers and interventional targets for AP rupture.
The microarray data were downloaded from the Gene Expression Omnibus (GEO) database and grouped into discovery and validation cohorts. In the discovery cohort, Weighted Gene Co-Expression Network Analysis was performed for finding co-expression modules, and the Metascape database was used to perform functional enrichment analysis. Differential Expression Genes analysis subsequently was performed in the validation cohort for verification of the obtained results. Common genes were introduced into Metascape database for protein-protein interaction and functional enrichment analysis. We constructed the miRNAs-mRNAs network with the hub genes. Moreover, gene expression profiles of peripheral blood mononuclear cells (PBMCs) from peripheral blood of patients with plaque rupture were analyzed by high-throughput sequencing, and the diagnostic power of hub genes was verified by receiver operating characteristic (ROC) analysis.
In the discovery cohort, the brown module in GSE28829 and the turquoise module in GSE163154 were the most significant co-expression modules. Functional enrichment analysis of shared genes suggested that "Neutrophil degranulation" was the most significantly enriched pathway. These conclusions were also demonstrated by the validation cohort. A total of 16 hub genes were identified. The miRNA-mRNA network revealed that hsa-miR-665 and hsa-miR-512-3p might regulate the "Neutrophil degranulation" pathway through and , which might play a significant role in AP progression and instability. Five hub genes, including , , , , and , showed significantly increased expression in PBMCs from patients with plaque rupture compared with controls. ROC analysis finally identified three hub genes , , and that could effectively distinguish patients with APs rupture from controls.
The present study demonstrated that the "neutrophil degranulation" signaling pathways and identified novel mRNA and miRNA candidates are closely associated with plaque progression and instability. The hub genes , , and may serve as biomarkers for the prospective prediction of AP rupture.
动脉粥样硬化斑块（AP）持续进展导致的斑块破裂和急性动脉粥样血栓形成是中风或心肌梗死等急性临床事件的主要促成因素。本文旨在探索AP进展和不稳定过程中的基因特征及潜在分子机制，并确定AP破裂的新型生物标志物和干预靶点。
从基因表达综合数据库（GEO）下载微阵列数据，并分为发现队列和验证队列。在发现队列中，进行加权基因共表达网络分析以寻找共表达模块，并使用Metascape数据库进行功能富集分析。随后在验证队列中进行差异表达基因分析以验证所得结果。将共同基因引入Metascape数据库进行蛋白质-蛋白质相互作用和功能富集分析。我们用枢纽基因构建了miRNAs-mRNAs网络。此外，通过高通量测序分析斑块破裂患者外周血中单个核细胞（PBMC）的基因表达谱，并通过受试者工作特征（ROC）分析验证枢纽基因的诊断能力。
在发现队列中，GSE28829中的棕色模块和GSE163154中的绿松石色模块是最显著的共表达模块。共享基因的功能富集分析表明，“中性粒细胞脱颗粒”是最显著富集的通路。验证队列也证实了这些结论。共鉴定出16个枢纽基因。miRNA-mRNA网络显示，hsa-miR-665和hsa-miR-512-3p可能通过和调节“中性粒细胞脱颗粒”通路，这可能在AP进展和不稳定中起重要作用。与对照组相比，包括、、、和在内的5个枢纽基因在斑块破裂患者的PBMC中表达显著增加。ROC分析最终确定了3个枢纽基因、和，它们可以有效区分AP破裂患者和对照组。
本研究表明，“中性粒细胞脱颗粒”信号通路以及鉴定出的新型mRNA和miRNA候选物与斑块进展和不稳定密切相关。枢纽基因、和可作为前瞻性预测AP破裂的生物标志物。
