Wang Yinyu, Shang Tingting, Cai Rui, Wang Cuiping
Department of Cardiology, Affiliated Hospital of Jiangsu University, Zhenjiang, People's Republic of China.
Department of Cardiology, The Affiliated Yancheng Maternity & Child Health Hospital of Yangzhou University, Yancheng, People's Republic of China.
J Inflamm Res. 2025 Jul 26;18:10029-10049. doi: 10.2147/JIR.S519114. eCollection 2025.
Atherosclerosis is the pathological basis of coronary heart disease, stroke, and peripheral arterial disease. Smooth muscle cells (SMCs) play a crucial role in atherosclerotic pathogenesis. However, effective drugs and therapy targeting SMCs for treating atherosclerosis are still lacking.
We utilized single-cell RNA sequencing (scRNA-seq) (GSE155512 and GSE159677) and array data (GSE43292 and GSE125771) to identify Scissor+ SMCs (SMCs positively associated with atherosclerosis) and Scissor- SMCs (SMCs negatively associated with atherosclerosis) by using Scissor package. We analyzed their functional changes, cell-cell communication, and differentiation potential. Machine learning techniques were employed to analyze the marker in SMCs of atherosclerosis. qRT-PCR was used to examine the expression of these genes in MOVAS stimulated by ox-LDL. Potential inhibitors of the identified proteins were predicted, and their binding sites were analyzed.
We identified 475 Scissor+ SMCs and 1363 Scissor- SMCs. Functional enrichment analysis revealed that Scissor+ SMCs exhibited downregulation of Rho-related pathways, while pro-inflammatory pathways were upregulated. Cell-cell communication analysis indicated tighter interactions between SMCs and endothelial cells. Differential expression analysis identified 20 genes highly expressed in both scRNA-seq and array data. The LASSO regression, random forest, support vector machine and receiver operating characteristic curve suggested a strong correlation between fatty acid-binding protein 4 (FABP4) and atherosclerosis. The qRT-PCR results showed that FABP4 was highly expressed in MOVAS stimulated by ox-LDL. Drug prediction revealed that (S)-RP-6306 acted as an inhibitor, via forming a polar bond with Arg-126. In vitro experiments confirmed that (S)-RP-6306 significantly reduced the expression of FABP4.
Scissor+ SMCs differed significantly from Scissor- SMCs in cellular function, cell-cell communication, and differentiation potential. The high expression of FABP4 in this subgroup of SMCs presented a promising therapeutic target for atherosclerosis, with (S)-RP-6306 showing potential as a drug targeting FABP4.
动脉粥样硬化是冠心病、中风和外周动脉疾病的病理基础。平滑肌细胞（SMC）在动脉粥样硬化发病机制中起关键作用。然而，针对SMC治疗动脉粥样硬化的有效药物和疗法仍然缺乏。
我们利用单细胞RNA测序（scRNA-seq）（GSE155512和GSE159677）和阵列数据（GSE43292和GSE125771），通过使用Scissor软件包来识别Scissor+ SMC（与动脉粥样硬化呈正相关的SMC）和Scissor- SMC（与动脉粥样硬化呈负相关的SMC）。我们分析了它们的功能变化、细胞间通讯和分化潜能。采用机器学习技术分析动脉粥样硬化SMC中的标志物。qRT-PCR用于检测氧化型低密度脂蛋白（ox-LDL）刺激的MOVAS中这些基因的表达。预测了所鉴定蛋白质的潜在抑制剂，并分析了它们的结合位点。
我们鉴定出475个Scissor+ SMC和1363个Scissor- SMC。功能富集分析显示，Scissor+ SMC的Rho相关通路下调，而促炎通路上调。细胞间通讯分析表明SMC与内皮细胞之间的相互作用更紧密。差异表达分析确定了20个在scRNA-seq和阵列数据中均高表达的基因。套索回归、随机森林、支持向量机和受试者工作特征曲线表明脂肪酸结合蛋白4（FABP4）与动脉粥样硬化之间存在强相关性。qRT-PCR结果显示，FABP4在ox-LDL刺激的MOVAS中高表达。药物预测显示，（S）-RP-6306作为抑制剂，通过与Arg-126形成极性键发挥作用。体外实验证实，（S）-RP-6306显著降低了FABP4的表达。
Scissor+ SMC在细胞功能、细胞间通讯和分化潜能方面与Scissor- SMC有显著差异。该亚组SMC中FABP4的高表达为动脉粥样硬化提供了一个有前景的治疗靶点，（S）-RP-6306显示出作为靶向FABP4的药物的潜力。
