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

Abstract

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.

Identification of immune-related hub genes and miRNA-mRNA pairs involved in immune infiltration in human septic cardiomyopathy by bioinformatics analysis

“…From the published articles, we also found that Chen et al ( 61 ), Kang et al ( 62 ), Gong et al ( 63 ), Li et al ( 64 ), and Wang et al ( 65 ). similarly applied bioinformatics approaches to study the hub genes in SCM.…”

“…similarly applied bioinformatics approaches to study the hub genes in SCM. First and foremost, our studies with Chen et al ( 61 ), Kang et al ( 62 ), Li et al ( 64 ), and Wang et al ( 65 ) used the human SCM dataset GSE79962 as an experimental dataset, but we innovatively combined immune cell marker genes with SCM differentially expressed genes to identify the biomarker role of IRHG in SCM; Secondly, we also used MCODE to identify the central clusters of SCM differentially expressed genes to explore modules that play an important interaction in SCM and their involved pathways; Thirdly, different from the studies of Kang et al ( 62 ) and Gong et al ( 63 ), we also extracted human samples to verify the expression of target genes, and used ROC curves to analyze the diagnosticity of target genes for SCM. Finally, a miRNA-IRHG pair that is different from previous studies and has an immunomodulatory role in SCM was obtained: miR-222-3p/THBS1.…”

A novel signature combing cuproptosis- and ferroptosis-related genes in sepsis-induced cardiomyopathy

“…In a recent bioinformatics analysis of sepsis-induced cardiomyopathy, POR was selected as the central gene and its expression level was higher than that of the control group. GSEA then demonstrated POR to have a close relationship with cardiac metabolism, necroptosis and apoptosis of cells in SIC ( Li et al, 2021 ). Solute carrier family 7 member 5 (SLC7A5), also known as L-type amino acid transporter (LAT1) ( Galluccio et al, 2013 ), is a sodium-independent high-affinity amino acid transporter.…”

The pathogenesis and potential therapeutic targets in sepsis

“…Additionally, necroptosis triggers inflammation and immunogenic events in different diseases by interacting with death receptors and diverse cytoplasmic protein kinases. Unlike necrosis, which usually results in irreversible pathological damage, necroptosis is employed by organisms to acquire appropriate levels of energy supply and promote cell regeneration 179,180 . Initially, defined as a type of TNF‐induced necrosis, necroptosis was subsequently recognized as a specific kinase‐dependent process after being effectively subdued by RIPK1 inhibitors 181–183 .…”