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. 2022 Oct 17:13:1032572.
doi: 10.3389/fgene.2022.1032572. eCollection 2022.

Regulatory mechanism of fibrosis-related genes in patients with heart failure

Yijing Tao  1   2 , ChengJie Gao  3 , Da Qian  4 , Donglai Cao  2 , Leng Han  2 , Ling Yang  1
Affiliations

Regulatory mechanism of fibrosis-related genes in patients with heart failure

Yijing Tao et al. Front Genet. .

Abstract

Background: Heart failure (HF) is a complex clinical syndrome characterized by the inability to match cardiac output with metabolic needs. Research on regulatory mechanism of fibrosis-related genes in patients with HF is very limited. In order to understand the mechanism of fibrosis in the development and progression of HF, fibrosis -related hub genes in HF are screened and verified. Methods: RNA sequencing data was obtained from the Gene Expression Omnibus (GEO) cohorts to identify differentially expressed genes (DEGs). Thereafter, fibrosis-related genes were obtained from the GSEA database and that associated with HF were screened out. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways analysis was carried out to analyze the biological function of fibrosis-related DEGs. The protein-protein interaction (PPI) network of hub genes was constructed via the STRING database. Moreover, the diagnostic value of hub genes for HF was confirmed using ROC curves and expression analysis. Finally, quantitative real time PCR was used to detect the expression levels of mRNAs. Results: A total of 3, 469 DEGs were identified closely related to HF, and 1, 187 fibrosis-related DEGs were obtained and analyzed for GO and KEGG enrichment. The enrichment results of fibrosis-related DEGs were consistent with that of DEGs. A total of 10 hub genes (PPARG, KRAS, JUN, IL10, TLR4, STAT3, CXCL8, CCL2, IL6, IL1β) were selected via the PPI network. Receiver operating characteristic curve analysis was estimated in the test cohort, and 6 genes (PPARG, KRAS, JUN, IL10, TLR4, STAT3) with AUC more than 0.7 were identified as diagnosis genes. Moreover, miRNA-mRNA and TF-mRNA regulatory networks were constructed. Finally, quantitative real time PCR revealed these 6 genes may be used as the potential diagnostic biomarkers of HF. Conclusion: In this study, 10 fibrosis-related hub genes in the HF were identified and 6 of them were demonstrated as potential diagnostic biomarkers for HF.

Keywords: cardiac remodeling; diagnosis; fibrosis; heart failure; hub gene.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

FIGURE 1
FIGURE 1
Identification and functional enrichment analysis of DEGs between the HF samples and control samples in GSE141910 datasets. Volcano plot (A) and heatmap (B) of DEGs. GO enrichment (C) and KEGG pathway enrichment results (D) of the DEGs. Green, downregulated; red, upregulated; grey, not differential expressed. DEGs, differentially expressed genes.
FIGURE 2
FIGURE 2
Functional enrichment analysis and exploring the interaction of fibrosis-related DEGs. Venn Diagram showed the intersection of DEGs and fibrosis-related genes (A). GO enrichment (B) and KEGG pathway enrichment results (C). PPI network of the interaction of fibrosis-related DEGs (D). PPI network of the top 100 genes and the top 10 genes with the highest degrees (E).
FIGURE 3
FIGURE 3
The ROC curve analysis and expression analysis of hub genes in train set and validation set. The expression of the hub genes between the HF and normal group in GSE141910 (A). ROC curve evaluated the diagnostic value of hub genes for HF in GSE141910 (B). The expression of the hub genes between the HF and normal group in GSE57338 (C).
FIGURE 4
FIGURE 4
The potential regulatory mechanisms of ultimately hub genes. The regulatory relationships between the target genes and their miRNAs (A). Green, downregulated; red, upregulated; Circle, hub gene; Triangle, miRNA. The interaction network consists of 4 hub genes and 8 TFs (B). Blue, downregulated; red, upregulated; Circle, hub genes; Triangle, Transcription Factor. The correlation analysis of 4 hub genes and their potential TFs (C).
FIGURE 5
FIGURE 5
Validation of the expression of 6 hub genes by quantitative real time PCR. The levels of IL-10 (A), JUN (B), KRAS (C), PPARG (D), STAT3 (E) and TLR4 (F) in plasma samples from patients with HF and healthy controls were measured by qPCR. Results were shown as mean ± SD. * p < 0.05 ** p < 0.01 vs. control. GAPDH was used as housekeeping gene.
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