Abstract
BackgroundDiabetic cardiomyopathy (DCM) is a specific form of cardiomyopathy that is independent of coronary artery disease and hypertension. Exploring the transcriptomics of DCM is of great significance for understanding the biology of the disease and for guiding new therapeutic targets for the potential therapeutic effect of spermine (SPM).Methods and ResultsBy using a mouse DCM model, we analyzed the transcriptome of the myocardium, before/after treatment with SPM. Using RNA sequencing (RNA-seq), we identified 1,318 differentially expressed genes (DEGs), with 636 being upregulated and 682 being downregulated in DCM compared to control check (CK). We then identified 1,393 DEGs, with 887 being upregulated and 506 being downregulated in SPM compared to DCM. Kyoto Encyclopedia of Genes And Genomes (KEGG) analysis demonstrated that the DEGs were significantly enriched in the immune system and signal transduction-related pathways. UpSet Venn analysis showed that 174 DEGs in DCM could be reversed by SPM, with 45 candidates related to immune system and related signal transduction pathways. Trend analysis demonstrated the dynamic changes in gene levels in DCM and SPM treatment, shown as 49 immune and signal transduction-related candidates were significantly enriched in some classical pathways, such as complement and coagulation cascades and phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K)-protein kinase B (Akt) signaling pathway. To further reveal the protective mechanism of SPM to DCM, we predicted 14 overlapped transcription factors (TFs) and their co-factors involved in gene transcription regulation and showed gene interaction with Cytoscape.ConclusionThe biomarkers and canonical pathways identified in this study may hold the key to understanding the mechanisms of DCM pathobiology and providing new targets for the therapeutic effect of SPM against DCM by targeting abnormal immune response and signal transduction.
Highlights
Diabetic cardiomyopathy (DCM) is closely associated with type 1 diabetes (T1D), which is characterized by hyperglycemia and results in low-grade systemic inflammation [1]
Mice were housed in a controlled environment (24 ± 1°C; 60 ± 10% relative humidity; fixed 12/12 h light/dark cycle) with food and water ad libitum and were randomized into three groups (n = 24 per group): [1] control check group (CK), 0.1 mol/L sterile citrate buffer was injected intraperitoneally; [2] diabetic cardiomyopathy model group (DCM), a single intraperitoneal injection of streptozotocin (STZ, 180 mg/kg, dissolved in 0.1 mol/L, pH 4.5 citric acid–citrate sodium buffer) was used to establish type 1 diabetes (T1D) model with normal diet fed for 12 weeks; and [3] spermine group (SPM), an injection of SPM (1 mg/kg/day) every day for 2 weeks prior to STZ injection; after which SPM was injected every other day for 12 weeks
Expressed genes (DEGs) in the myocardium evaluated by RNAseq analysis showed that 636 genes were upregulated, while 682 genes were downregulated by at least 1.5-fold in the diabetic cardiomyopathy (DCM) model group compared to control check (CK) group, while 887 genes were upregulated while 506 genes were downregulated in the spermine (SPM) group compared to DCM
Summary
Diabetic cardiomyopathy (DCM) is closely associated with type 1 diabetes (T1D), which is characterized by hyperglycemia and results in low-grade systemic inflammation [1]. Studies have shown that immune and its related signal transduction pathways, oxidative stress, fibrosis, coronary endothelial cells dysregulation, exosomes, abnormal mitochondrial calcium handling, and some other factors play a potentially important role in the pathogenesis of diabetes and dilated cardiomyopathy, but the exact mechanism is not yet fully understood [1–4]. We have previously found that the intracellular content of SPM was decreased significantly in cardiomyocytes of T1D rats, resulting in myocardial energy metabolism disorder, oxidative stress, and myocardial fibrosis, which can be alleviated by exogenous SPM treatment [9–12]. The effect of SPM on DCM, especially on immunity and its related signal transduction pathways, needs to be further explored. Exploring the transcriptomics of DCM is of great significance for understanding the biology of the disease and for guiding new therapeutic targets for the potential therapeutic effect of spermine (SPM)
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