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. 2022 Sep;10(18):1008.
doi: 10.21037/atm-22-4372.

Inhibitory effect of CUL1 on atherosclerosis through the p53 pathway

Xi Zhang #  1 , Youwei Lu #  1 , Wei Jiang  2 , Qianhong Yang  1
Affiliations

Inhibitory effect of CUL1 on atherosclerosis through the p53 pathway

Xi Zhang et al. Ann Transl Med. 2022 Sep.

VSports app下载 - Abstract

Background: Atherosclerosis (AS) is a serious chronic condition associated with cardiovascular and cerebrovascular diseases VSports手机版. Research on AS is currently lacking, and there is a need to increase research to improve the diagnosis, treatment, and prognosis of AS. Therefore, the aim of the present study was to explore the molecular mechanism and identify potential biomarkers in AS. .

Methods: First, we downloaded the GSE28829 dataset and screened differentially expressed genes (DEGs). Then, DEGs were analyzed by functional enrichment analysis and protein-protein interaction (PPI) networks to determine hub genes. The key gene for AS was identified following the expression analysis of AS, clinical correlation with immune factors, the gene set enrichment analysis (GSEA) enrichment pathway, and receiver-operating characteristic curve analysis V体育安卓版. In functional experiments, correlations between cullin 1 (CUL1), cytokines, and downstream targets in AS were investigated. .

Results: We identified 595 upregulated and 391 downregulated DEGs enriched in neutrophil degranulation, the B-cell receptor signaling pathway, cell-matrix adhesion, and fatty acid degradation V体育ios版. Through PPI, we identified 7 hub genes for the expression analysis, immunoassay, and GSEA. Finally, CUL1 was identified as the inhibitory gene in AS associated with immune factors, and was found to have a strong prognostic prediction ability. The results indicated that CUL1 upregulated interleukin (IL)-6, IL-1β, and tumor necrosis factor-α concentrations, and weakened the cell proliferation of AS. It was also found that CUL1 exerted its inhibitory function in AS by the p53 pathway. .

Conclusions: The findings of the present study indicate that CUL1 is a suppressing gene in AS, and has the potential to be a therapeutic and prognostic biomarker for AS VSports最新版本. .

Keywords: Atherosclerosis (AS); cullin 1 (CUL1); differentially expressed genes; immunoassay; p53 pathway. V体育平台登录.

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VSports最新版本 - Conflict of interest statement

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://atm V体育官网入口. amegroups. com/article/view/10. 21037/atm-22-4372/coif). The authors have no conflicts of interest to declare.

Figures

Figure 1
Figure 1
Visualization, functional enrichment, and PPI network analysis of DEGs. (A) Heatmap showing the expressions of DEGs in the case (red) and control groups (purple). (B,C) Gene Ontology enrichment analysis of upregulated and downregulated DEGs. (D,E) Enrichment pathways of upregulated and downregulated DEGs in Kyoto Encyclopedia of Genes and Genomes. (F,G) PPI network map of upregulated and downregulated DEGs. PPI, protein-protein interaction; DEGs, differentially expressed genes.
Figure 2
Figure 2
Screening of upregulated and downregulated hub genes. (A) Upregulated hub genes are shown in yellow. (B-E) Boxplots of ITGAM, ITGB2, VAMP8, and C3AR1 expression analyses. ***P<0.001. ITGAM, integrin subunit alpha M; ITGB2, integrin subunit beta 2; VAMP8, vesicle associated membrane protein 8; C3AR1, complement C3a receptor 1.
Figure 3
Figure 3
Screening of downregulated hub genes. (A) Downregulated hub genes are shown in yellow. (B-D) Boxplots of SKP1, UBC, CUL1 expression analyses. **P<0.01, ***P<0.001. SKP1, S-phase kinase associated protein 1; UBC, ubiquitin C; CUL1, cullin 1.
Figure 4
Figure 4
Heatmap of the correlation between the 7 hub genes and immune factors. Horizontal and vertical coordinates represent genes, and the different colors represent the correlation coefficient. Blue represents a positive correlation, and red represents a negative correlation. The darker the color, the stronger the correlation. *P<0.05, **P<0.01. Immune factors included (A) chemokine, (B) immunoinhibitor, (C) immunostimulator, (D) MHC molecule, (E) receptor. MHC, major histocompatibility complex.
Figure 5
Figure 5
GSEA analysis and ROC curve analysis of upregulated hub genes. (A,B) Enrichment pathways and ROC curves of ITGAM. AUC =0.903. (C,D) Enrichment pathways and ROC curves of ITGB2. AUC =0.913. (E,F) Enrichment pathways and ROC curves of VAMP8. AUC =0.944. (G,H) Enrichment pathways and ROC curves of C3AR1. AUC =0.969. GSEA, gene set enrichment analysis; ROC, receiver-operating characteristic; AUC, area under the ROC curve; ES, Enrichment score; NP, NOM P-value; TPR, true positive rate; FPR, false positive rate.
Figure 6
Figure 6
GSEA analysis and ROC curve analysis of downregulated hub genes. (A,B) Enrichment pathways and ROC curves of SKP1. AUC =0.938. (C,D) Enrichment pathways and ROC curves of UBC. AUC =0.844. (E,F) Enrichment pathways and ROC curves of CUL1. AUC =0.851. GSEA, gene set enrichment analysis; ROC, receiver-operating characteristic; AUC, area under the ROC curve; CUL1, cullin 1; ES, Enrichment score; NP, NOM P-value; TPR, true positive rate; FPR, false positive rate.
Figure 7
Figure 7
CUL1 could inhibit cell proliferation in AS. (A) Relative expressions of CUL1 with 50 and 100 µg/mL in HUVECs. (B) Over-CUL1 was transfected into HUVECs. (C) CUL1 could inhibit cell proliferation in AS. (D) Over-expressed CUL1 could elevate the concentrations of cytokines. #P<0.05, compared with oxLDL group; *P<0.05, **P<0.01, compared with control group. CUL1, cullin 1; HUVECs, human umbilical vein endothelial cells; AS, atherosclerosis; oxLDL, oxidized low-density lipoprotein; NC, negative control; OD, optical density; IL, interleukin; TNF, tumor necrosis factor.
Figure 8
Figure 8
CUL1 inhibits the progression of AS by the p53 pathway. (A) Relative expression levels of CUL1 in each group were detected. (B-G) Expressions of the p53 (B), MDM2 (C), Bax (D), caspase-9 (E), caspase-3 (F), and p21 (G) pathways in each group. (H) CCK-8 demonstrated that PFT-α could promote cell growth in AS. *P<0.05 compared with normal; #P<0.05, ##P<0.01 compared with oxLDL. CUL1, cullin 1; AS, atherosclerosis; oxLDL, oxidized low-density lipoprotein; PET-α, pifithrin-α; NC, negative control; OD, optical density; CCK-8, cell counting kit-8.
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