Abstract
BACKGROUND
Patients with dilated cardiomyopathy (DCM) often have heart failure, which seriously affects their health and quality of life. Some studies have suggested that DCM has a genetic basis, although the molecular mechanism involved have yet to be fully characterized. Cuproptosis is a newly defined type of programmed cell death thought to be involved in the pathogenesis and progression of cardiovascular disease. The aim of this study was therefore to identify biomarkers associated with cuproptosis in DCM, and the potential pathological mechanisms involving cuproptosis in cardiomyocytes.
MATERIALS
Cuproptosis-related genes (CRGs) were identified from previous publications. The GSE141910 dataset was downloaded from the GEO database.
METHODS
Consistency clustering was performed according to cuproptosis gene expression. Differentially expressed genes (DEGs) were identified using the limma package, and key genes were identified using the weighted gene co-expression network analysis (WGCNA) method. These were then subjected to immune infiltration analysis, enrichment analysis, and prediction of the key associated transcription factors. Consistency clustering identified three cuproptosis clusters. The DEGs in each were identified using limma, and the most critical module was obtained using WGCNA. Three machine learning algorithms (SVM-RFE, LASSO, and RF) were then used to screen genes in the modules generated by WGCNA, with the key genes obtained by intersection. Finally, GSEA enrichment analysis of the key genes was performed and a ceRNA network was constructed.
RESULTS
Five key CRGs were identified (C1QTNF7, LYVE1, FRZB, AQP10 and FNDC1), with only LYVE1 showing upregulated expression in DCM. These genes were closely related to T cell and NK cell infiltration. Expression of the C1QTNF7 and FRZB genes showed the highest correlation, and both were closely related to the calcium signaling pathway and mitochondrial dysfunction. Both genes may be jointly regulated by mir-130a-3p.
CONCLUSION
C1QTNF7 and FRZB may be downregulated by mir-130a-3p, resulting in low expression. The two genes may act synergistically to cause calcium disorders, which in turn regulates the level of copper ions in mitochondria and induces cuproptosis. This can damage mitochondrial function, cause myocardial dysfunction, and apoptosis, thus promoting the development of DCM.