Integrated bioinformatic analysis reveals immune molecular markers and potential drugs for diabetic cardiomyopathy

Abstract

Diabetic cardiomyopathy (DCM) is a pathophysiological condition induced by diabetes mellitus that often causes heart failure (HF). However, their mechanistic relationships remain unclear. This study aimed to identify immune gene signatures and molecular mechanisms of DCM. Microarray data from the Gene Expression Omnibus (GEO) database from patients with DCM were subjected to weighted gene co-expression network analysis (WGCNA) identify co-expression modules. Core expression modules were intersected with the immune gene database. We analyzed and mapped protein-protein interaction (PPI) networks using the STRING database and MCODE and filtering out 17 hub genes using cytoHubba software. Finally, potential transcriptional regulatory factors and therapeutic drugs were identified and molecular docking between gene targets and small molecules was performed. We identified five potential immune biomarkers: proteosome subunit beta type-8 (PSMB8), nuclear factor kappa B1 (NFKB1), albumin (ALB), endothelin 1 (EDN1), and estrogen receptor 1 (ESR1). Their expression levels in animal models were consistent with the changes observed in the datasets. EDN1 showed significant differences in expression in both the dataset and the validation model by real-time quantitative PCR (qPCR) and Western blotting(WB). Subsequently, we confirmed that the potential transcription factors upstream of EDN1 were PRDM5 and KLF4, as its expression was positively correlated with the expression of the two transcription factors. To repurpose known therapeutic drugs, a connectivity map (CMap) database was retrieved, and nine candidate compounds were identified. Finally, molecular docking simulations of the proteins encoded by the five genes with small-molecule drugs were performed. Our data suggest that EDN1 may play a key role in the development of DCM and is a potential DCM biomarker.

Exploring Potentilla nepalensis Phytoconstituents: Integrated Strategies of Network Pharmacology, Molecular Docking, Dynamic Simulations, and MMGBSA Analysis for Cancer Therapeutic Targets Discovery

“…Problems in Nf-kB1 activation have been linked to numerous inflammatory diseases, while continuous inhibition affects immune cell development or delayed cell growth [ 12 ]. It is widely used as a therapeutic target in diabetic cardiomyopathy [ 13 ]. Thus, inhibition of the Nf-kB1 helps to reduce the anti-inflammatory activity of targeting Nf-kB1 in the associated pathways [ 14 , 15 ].…”

Linking Fatty Acid Metabolism to Diabetic Cardiomyopathy: The Role of Mitochondrial Dysfunction and Immune Microenvironment Alterations, a Bioinformatics Approach

“…The relationship between metabolic status and immunological state is complex and tightly intertwined [45]. Diabetes mellitus, is a metabolic disease, exerts profound effects on immune responses and substrate energy metabolism [46][47][48]. In diabetes, both innate and adaptive immune responses are profoundly affected, particularly in the context of DCM, where in ammation-related tissue injury triggers activation of immune responses in the heart [45].…”

Integrated bioinformatics analysis for identifying key genes and pathways in female and male patients with dilated cardiomyopathy

“…Some experimental results have demonstrated the mRNA or protein expression levels of the seven genes. Among the identified seven up-regulated genes, researches have shown that the levels of DUOX2, CXCL10 and CD40LG expression were significantly higher in patients with DCM 32 , 74 , 75 , and ESR1 and COL1A1 were substantially up-regulated in the mouse model of DCM 22 , 76 . In addition, the expression levels of CXCL11 and OLR1 have been proved to be elevated in heart failure patients 77 , 78 .…”