Department of Pharmacology, College of Pharmacy, Army Medical University (Military Medical University), Chongqing, China .
J Cardiovasc Pharmacol. 2024 Mar 1;83(3):276-288. doi: 10.1097/FJC.0000000000001528.
Atherosclerotic plaque accounts for major adverse cardiovascular events because of its vulnerability. The classically activated macrophage (M1) and alternatively activated macrophage (M2) are implicated in the progression and regression of plaque, respectively. However, the therapeutic targets related to M2 macrophages still remain largely elusive. In this study, cell-type identification by estimating relative subsets of RNA transcripts and weighted gene coexpression network analysis algorithms were used to establish a weighted gene coexpression network for identifying M2 macrophage-related hub genes using GSE43292 data set. The results showed that genes were classified into 7 modules, with the blue module (Cor = 0.67, P = 3e-05) being the one that was most related to M2 macrophage infiltration in advanced plaques, and then 99 hub genes were identified from blue module. Meanwhile, 1289 differentially expressed genes were produced in GSE43292 data set. Subsequently, the intersection genes of hub genes and differentially expressed genes, including AKTIP , ASPN , FAM26E , RAB23 , PLS3 , and PLSCR4 , were obtained by Venn diagrams and named as key genes. Further validation using data sets GSE100927 and GSE41571 showed that 6 key genes all downregulated in advanced and vulnerable plaques compared with early and stable plaque samples (|Log2 (fold change)| > 0.5, P < 0.05 or 0.001), respectively. Receiver operator characteristic curve analysis indicated that the 6 key genes might have potential diagnostic value. The validation of key genes in the model in vitro and in vivo also demonstrated decreased mRNA expressions of AKTIP , ASPN , FAM26E , RAB23 , PLS3 , and PLSCR4 ( P < 0.05 or 0.001). Collectively, we identified AKTIP, ASPN, FAM26E, RAB23, PLS3, and PLSCR4 as M2 macrophage-related key genes during atherosclerotic progression, proposing potential intervention targets for advanced atherosclerotic plaques.
动脉粥样硬化斑块因其易损性而导致主要不良心血管事件。经典激活的巨噬细胞（M1）和交替激活的巨噬细胞（M2）分别参与斑块的进展和消退。然而，与 M2 巨噬细胞相关的治疗靶点在很大程度上仍然难以捉摸。在这项研究中，通过估计 RNA 转录物的相对亚群和加权基因共表达网络分析算法对细胞类型进行鉴定，使用 GSE43292 数据集建立了一个加权基因共表达网络，以鉴定与 M2 巨噬细胞浸润相关的枢纽基因。结果表明，基因被分为 7 个模块，其中蓝色模块（Cor = 0.67，P = 3e-05）与高级斑块中 M2 巨噬细胞浸润最相关，然后从蓝色模块中鉴定出 99 个枢纽基因。同时，在 GSE43292 数据集中产生了 1289 个差异表达基因。随后，通过 Venn 图获得了枢纽基因和差异表达基因的交集基因，包括 AKTIP、ASPN、FAM26E、RAB23、PLS3 和 PLSCR4，并将其命名为关键基因。使用数据集 GSE100927 和 GSE41571 进一步验证表明，与早期和稳定斑块样本相比，6 个关键基因在高级和易损斑块中均下调（|Log2（fold change）|>0.5，P<0.05 或 0.001）。受试者工作特征曲线分析表明，这 6 个关键基因可能具有潜在的诊断价值。体外和体内模型中关键基因的验证也表明，AKTIP、ASPN、FAM26E、RAB23、PLS3 和 PLSCR4 的 mRNA 表达均降低（P<0.05 或 0.001）。综上所述，我们鉴定出 AKTIP、ASPN、FAM26E、RAB23、PLS3 和 PLSCR4 是动脉粥样硬化进展过程中与 M2 巨噬细胞相关的关键基因，为晚期动脉粥样硬化斑块提供了潜在的干预靶点。
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