2021) Integrated weighted gene co-expression network analysis uncovers STAT1(signal transducer and activator of transcription 1) and IFI44L (interferon-induced protein 44-like) as key genes in pulmonary arterial hypertension,
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Object: Ischemic cardiomyopathy (ICM), with high morbidity and mortality, is the most common cause of heart failure. Cardiovascular remodeling secondary to chronic myocardial ischemia is the main cause of its progression. A recently identified type of programmed cell death called necroptosis is crucial in the development of various cardiovascular diseases. However, the function role of necroptosis in cardiac remodeling of ICM has not been elucidated. Our study aimed to screen for genes associated with necroptosis and construct a risk score to assess the progression and evaluate the prognosis of ICM patients, and further to search for potentially therapeutic drugs.Methods: The gene expression profiling was obtained from the GEO database. LASSO regression analysis was used to construct necroptosis-related gene signatures associated with ICM progression and prognosis. TF-gene and miRNA-gene networks were constructed to identify the regulatory targets of potential necroptosis-related signature genes. Pathway alterations in patients with high necroptosis-related score (NRS) were analyzed by GO, KEGG, GSEA analysis, and immune cell infiltration was estimated by ImmuCellAI analysis. CMap analysis was performed to screen potential small molecule compounds targeting patients with high NRS. Independent risk analyses were performed using nomograms.Results: Six necroptosis-related signature genes (STAT4, TNFSF10, CHMP5, CHMP18, JAK1, and CFLAR) were used to define the NRS, with areas under the ROC curves of 0.833, 0.765, and 0.75 for training test, test set, and validation set, respectively. Transcription factors FOXC1 and hsa-miR-124-3p miRNA may be regulators of signature genes. Patients with higher NRS have pathway enriched in fibrosis and metabolism and elevated nTreg cells. AZD-7762 may be an effective drug to improve the prognosis of patients with high NRS. A feature-based nomogram was constructed from which patients could derive clinical benefit.Conclusion: Our results reveal 6 necroptosis gene signatures that can evaluate the progression and prognosis of ICM with high clinical value, and identify potential targets that could help improve cardiovascular remodeling.
The development of dilated cardiomyopathy (DCM) is accompanied by a series of metabolic disorders, resulting in myocardial remodeling or exacerbation, while the mechanism remains not completely clear. This study was to find out the key metabolism-related genes involved in the onset of DCM, providing new insight into the pathogenesis of this disease. The datasets of GSE57338, GSE116250, and GSE5406 associated with hearts of patients with DCM were downloaded from the Gene Expression Omnibus database. GSE57338 was analyzed to screen out metabolism-related differentially expressed genes (DEGs), while GSE116250 and GSE5406 were utilized to verify the optimal genes through R software. Support vector machine recursive feature elimination algorithm and least absolute shrinkage and selection operator algorithm were used to determine key genes. Finally, 6 of 39 metabolism-related DEGs were screened out and identified as the optimal genes. After quantitative reverse-transcription polymerase chain reaction (qRT-PCR) validation performed on the samples drawn from the left ventricles of human hearts, it showed that only the expression of oxoglutarate dehydrogenase-like (OGDHL) increased while PLA2G2 decreased significantly in patients with DCM compared with non-failing donors, respectively. Furthermore, the higher OGDHL protein expression, except the change of PLA2G2, was also found in DCM hearts, and its mRNA expression was negatively correlated with myocardial Masson’s scores (r = –0.84, P = 0.009) and left ventricular end-diastolic diameter (LVEDd; r = –0.82, P = 0.014), which might be regulated by miR-3925-5p through further bioinformatics prediction and qRT-PCR verification. The data then suggested that the metabolism-related gene OGDHL was associated with myocardial fibrosis of DCM and probably a biomarker for myocardial remodeling in patients with DCM.
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