Investigation of crucial genes and mitochondrial function impairment in diabetic cardiomyopathy.

BACKGROUND: Diabetic cardiomyopathy (DCM) is a special type of cardiovascular disease, termed as a situation of abnormal myocardial structure and function that occurs in diabetic patients. However, the most fundamental mechanisms of DCM have not been fully explicated, and useful targets for the therapeutic strategies still need to be explored. METHODS: In the present study, we combined bioinformatics analysis and in vitro experiments throughout the process of DCM. Differentially Expressed Genes (DEGs) analysis was performed and the weighted gene co-expression network analysis (WGCNA) was constructed to determine the crucial genes that were tightly connected to DCM. Additionally, Functional enrichment analysis was conducted to define biological pathways. To identify the specific molecular mechanism, the human cardiomyocyte cell line (AC16) was stimulated by high glucose (HG, 50 mM D-glucose) and used to imitate DCM condition. Then, we tentatively examined the effect of high glucose on cardiomyocytes, the expression levels of crucial genes were further validated by in vitro experiments. RESULTS: Generally, NPPA, IGFBP5, SERPINE1, and C3 emerged as potential therapeutic targets. Functional enrichment analysis performed by bioinformatics indicated that the pathogenesis of DCM is mainly related to heart muscle contraction and calcium (Ca2+) release activation. In vitro, we discovered that high glucose treatment induced cardiomyocyte injury and exacerbated mitochondrial dysfunction remarkably. CONCLUSION: Our research defined four crucial genes, as well as determined that mitochondrial function impairment compromises calcium homeostasis ultimately resulting in contractile dysfunction is a central contributor to DCM progression. Hopefully, this study will offer more effective biomarkers for DCM diagnosis and treatment.

Detecting imperative genes and infiltrating immune cells in chronic Chagas cardiomyopathy by bioinformatics analysis.

Chronic Chagas cardiomyopathy (CCC) is an acquired inflammatory cardiomyopathy triggered by the protozoan Trypanosoma cruzi infection. Although microvascular and neurogenic dysfunction and inflammation with persistent parasite presence in the heart may play a major pathogenetic role, little is known about the overall picture of gene co-expression regulating CCC. In this study, we aimed to explore the key biological pathways, hub genes and the landscope of infiltrating immune cells associated with inflammation in chronic Chagas cardiomyopathy. A weighted gene co-expression network analysis (WGCNA) was conducted based on the gene expression profiles from patients with and without chronic Chagas cardiomyopathy (GSE84796). Twelve coexpression modules were identified from the top 25% variant genes. Among them, the turquoise and black module were significantly positively correlated with CCC, which were highly enriched in Th1 and Th2 cell differentiation, the Cytokine-cytokine receptor interaction,NF-kappa B signaling pathway and T cell receptor signaling pathway. In addition, four genes (TBX21, ZAP70,IL2RB and CD69) were selected as candidate hub genes. Gene expression for hub genes were higher in CCC tissues compared to tissues from healthy controls. Additionally, gene set enrichment analysis (GSEA) analysis showed that high expressions of these hub genes were significantly correlated with interferon α response and interferon γ response. The microarray dataset GSE41089 further confirmed that although CD69 was not detected, the expression of TBX21, IL2RB and ZAP70 was also significantly up-regulated in the CCC mice compared to controls. We further studied the immune cells infiltration in CCC patients with CIBERSORT. The fraction of Mast cells activated,T cells CD8 and T cells gamma delta were significantly increased in CCC patients compared with control. Our research provides a more effective understanding of the pathogenesis of CCC and could help in future strategies for new diagnostic and therapeutic approaches for CCC patients.

Identification of Crucial Genes and Infiltrating Immune Cells Underlying Sepsis-Induced Cardiomyopathy via Weighted Gene Co-Expression Network Analysis.

Sepsis-induced cardiomyopathy (SIC), with a possibly reversible cardiac dysfunction, is a potential complication of septic shock. Despite quite a few mechanisms including the inflammatory mediator, exosomes, and mitochondrial dysfunction, having been confirmed in the existing research studies we still find it obscure about the overall situation of gene co-expression that how they can affect the pathological process of SIC. Thus, we intended to find out the crucial hub genes, biological signaling pathways, and infiltration of immunocytes underlying SIC. It was weighted gene co-expression network analysis that worked as our major method on the ground of the gene expression profiles: hearts of those who died from sepsis were compared to hearts donated by non-failing humans which could not be transplanted for technical reasons (GSE79962). The top 25 percent of variant genes were abstracted to identify 10 co-expression modules. In these modules, brown and green modules showed the strongest negative and positive correlation with SIC, which were primarily enriched in the bioenergy metabolism, immunoreaction, and cell death. Next, nine genes (LRRC39, COQ10A, FSD2, PPP1R3A, TNFRSF11B, IL1RAP, DGKD, POR, and THBS1) including two downregulated and seven upregulated genes which were chosen as hub genes that meant the expressive level of which was higher than the counterparts in control groups. Then, the gene set enrichment analysis (GSEA) demonstrated a close relationship of hub genes to the cardiac metabolism and the necroptosis and apoptosis of cells in SIC. Concerning immune cells infiltration, a higher level of neutrophils and B cells native and a lower level of mast cells resting and plasma cells had been observed in patients with SIC. In general, nine candidate biomarkers were authenticated as a reliable signature for deeper exploration of basic and clinical research studies on SIC.