CD63 and C3AR1: The Potential Molecular Targets in the Progression of Septic Shock

The molecular mechanism of septic shock is unknown. We studied the pathogenesis of septic shock and provide a novel strategy for treating and improving the prognosis of septic shock.

Gluten-Sensitive Enteropathy (GSE) 131761, GSE119217, GSE26378 datasets were downloaded from the Gene Expression Omnibus (GEO) database. The three datasets included 204 septic shock samples and 48 normal samples. The R packages "affy" and "limma" were employed to identify the differently expressed genes (DEGs) between septic shock and normal samples. Weighted gene co-expression network analysis (WGCNA) was performed to search for modules that play an important role in septic shock. Functional annotation of DEGs and construction and analysis of hub genes were used to explore the pathomechanism of septic shock. The receiver operating characteristic (ROC) curves were obtained using MedCalc software. The drug molecules that could regulate hub genes associated with septic shock were searched for in the CMap database. An animal model of septic shock was constructed to analyze the role of these hub genes.

The merged series contained 321 up-regulated and 255 down-regulated genes. WGCNA showed the brown module had the highest correlation with the status of septic shock. GO and KEGG enrichment analysis results of the brown module genes showed they were mainly enriched in "leukocyte differentiation", "Ras-proximate-1 (Rap1) signaling pathway", and "cytokine-cytokine receptor interaction". Through construction and analysis of a protein-protein interaction (PPI) network, cluster of differentiation 63 (CD63) and complement component 3a receptor 1 (C3AR1) were identified as hub genes of septic shock. The area under curve (AUC) of C3AR1 for the septic shock is 0.772 (P<0.001), and the AUC of CD63 for the septic shock is 0.871 (P<0.001). Small molecule drugs were filtered by the number of instances (n>3) and P-values <0.05, including "monensin", "verteporfin", "ikarugamycin", "tetrahydroalstonine", "cefamandole", "etoposide". In the animal model, the relative expression levels of interleukin-6 (IL-6), Tumor Necrosis Factor-α (TNF-α), and lactic acid were significantly higher in the septic shock group compared with the control group. Results of Real Time Quantitative PCR (RT-qPCR) and enzyme-linked immunosorbent assay (ELISA) analysis for CD63 and C3AR1 showed that their relative expression levels were significantly lower in the septic shock group compared with the control group (P<0.05).

CD63 and C3AR1 are significant hub genes of septic shock and may represent potential molecular targets for future studies of septic shock.