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Quantitative Analysis and Characterization of Atherosclerotic Lesions in the Murine Aortic Sinus
Published on: December 7, 2013
Identification of M2 Macrophage-Related Key Genes in Advanced Atherosclerotic Plaques by Network-Based Analysis
Yao Yuan1, Peng Wang, Haigang Zhang
1Department of Pharmacology, College of Pharmacy, Army Medical University (Military Medical University), Chongqing, China .
Abstract:
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.
Insights
Researchers identified six key genes (AKTIP, ASPN, FAM26E, RAB23, PLS3, PLSCR4) linked to M2 macrophages in atherosclerotic plaque progression. These genes, downregulated in advanced plaques, offer potential therapeutic targets for cardiovascular events.
Area of Science:
- Cardiovascular Biology
- Immunology
- Genomics
Background:
- Atherosclerotic plaques contribute to major adverse cardiovascular events due to their vulnerability.
- Classically activated (M1) and alternatively activated (M2) macrophages influence plaque progression and regression, respectively.
- Therapeutic targets associated with M2 macrophages in atherosclerosis remain largely unidentified.
Purpose of the Study:
- To identify M2 macrophage-related hub genes in atherosclerotic plaques.
- To determine key genes associated with atherosclerotic plaque progression and vulnerability.
- To evaluate the diagnostic and therapeutic potential of identified key genes.
Main Methods:
- Weighted gene coexpression network analysis (WGCNA) was applied to the GSE43292 dataset to identify M2 macrophage-related modules and hub genes.
- Differential gene expression analysis was performed on the GSE43292 dataset.
- Venn diagrams were used to find the intersection of hub genes and differentially expressed genes. Validation was conducted using datasets GSE100927 and GSE41571, along with in vitro and in vivo models.
Main Results:
- A weighted gene coexpression network was constructed, identifying a blue module significantly correlated with M2 macrophage infiltration in advanced plaques.
- Nine-nine hub genes were identified within the blue module. Intersection with 1289 differentially expressed genes yielded six key genes: AKTIP, ASPN, FAM26E, RAB23, PLS3, and PLSCR4.
- These six key genes were consistently downregulated in advanced and vulnerable plaques compared to early and stable plaques, exhibiting potential diagnostic value and validated decreased mRNA expression in vitro and in vivo.
Conclusions:
- AKTIP, ASPN, FAM26E, RAB23, PLS3, and PLSCR4 were identified as key genes related to M2 macrophages in atherosclerotic progression.
- The downregulation of these genes in advanced atherosclerotic plaques suggests their role in plaque vulnerability.
- These identified key genes represent potential novel therapeutic targets for intervention in advanced atherosclerotic plaques.
