HF is a common manifestation of organ failure in sepsis and septic shock. However, the common molecular mechanisms underlying sepsis and HF are largely unknown. This study explored the shared gene signatures of sepsis and HF and elucidated their related regulatory mechanisms via integrated analysis of multiple microarray data and a series of bioinformatics analyses. Four hub-shared genes of the two diseases were identified, including RRS1, IMP4, RPLP0, and NOP16, which had high diagnostic performance, with AUC values higher than 0.7 in the four datasets. Moreover, there was a significantly negative correlation between RRS1 and M0 macrophages and between IMP4 macrophages and plasma cells in the two diseases, and the hub shared genes were significantly enriched in ribosome assembly and biogenesis processes. These findings reveal the common pathogenesis of the two diseases.
With the rapid development of microarray technology and bioinformatics analysis, expression data of thousands of genes can be quickly measured and analyzed in various diseases, which will help researchers to elucidate disease pathogenesis at the genetic level (Gong et al. 2020; Zhou et al. 2020). In this study, we for the first time explored the common mechanisms of sepsis and HF using WGCNA, which is an approach that has been widely applied to identify shared risk genes and mechanisms related to diverse disease phenotypes (Peng et al. 2022; Xu et al. 2022; Zhu et al. 2020). WGCNA revealed five sepsis-related modules containing 2972 genes and three HF-related modules containing 982 genes, and 170 shared genes of the two diseases were obtained by further intersection analysis. These genes may be common genetic mechanisms of sepsis and HF. To understand their possible biological function, we performed functional enrichment analysis and found that these shared genes were significantly enriched in GO biological process functions such as macrophage activation. Macrophages are fundamental components of inflammatory and fibrotic responses following myocardial infarction. Abnormal macrophage activation contributes to adverse cardiac events such as exacerbated fibrosis and HF (Shivshankar et al. 2014; Yonebayashi et al. 2020). In addition, macrophage activation can cause release of multiple proinflammatory cytokines, such as IL-1β, IL-6 and TNF-α, and production of excessive reactive oxygen species, leading to the inflammatory cascade in sepsis (Chen et al. 2019). Given the key role of macrophage activation in sepsis and HF, we speculate that these shared genes may contribute to sepsis and septic HF via regulation of macrophage activation.
To explore the core shared genes of the two diseases, we conducted PPI analysis for the shared genes of the two diseases and subsequent expression validation using external validation datasets (GSE65682 and GSE84796). Finally, four hub-shared genes of two diseases were identified, including RRS1, IMP4, RPLP0, and NOP16, which may be core genes mediating development of sepsis and septic HF. RRS1, a ribosomal protein, has been revealed to play a key role in ribosome biosynthesis, the cell cycle, and the ribosomal stress response, which affect the p53 signaling pathway. Aberrant expression of RRS1 is implicated in development of Huntington’s disease and multiple cancers (Hua et al. 2021). Moreover, the p53 signaling pathway is implicated in sepsis (Ma et al. 2016), sepsis-induced cardiomyopathy (Chen et al. 2022) and HF (Shimizu et al. 2012; Yoshida et al. 2015). However, it has not been investigated whether RRS1 contributes to sepsis and HF via the p53 signaling pathway, which merits further study. RPLP0 is also a ribosomal protein. Accumulating evidence has revealed that RPLP0 participates in multiple cancers (Chang and Xu 2022; Teller et al. 2015). RPLP0 has also been identified as a key regulator of neonatal sepsis (Bu et al. 2020). IMP4 is a component of U3 small nucleolar ribonucleoproteins that have been shown to play significant roles at telomeres (Hsieh et al. 2007). IMP4 was recently verified to be involved in the malignancy of lung cancer and is suggested to be a novel target (Li et al. 2022; Liu et al. 2021). NOP16, also known as HSPC111, is related to poor clinical outcomes in patients with breast cancer (Butt et al. 2008). Moreover, GSEA showed that ribosome biogenesis and assembly processes were significantly enriched in the groups with high expression of these hub-shared genes. Ribosomes are the sites of protein synthesis, and ribosome biogenesis is associated with diverse biological functions, such as cell proliferation and apoptosis (Kang et al. 2021). Abnormal ribosome biogenesis affects various ribosome-related diseases, such as bacterial resistance and cardiovascular diseases, and targeting ribosome biogenesis may be a potential therapy for these diseases (Jiao et al. 2023). These data indicate that these hub-shared genes may contribute to sepsis and HF by affecting ribosome biogenesis and assembly processes. Furthermore, these genes were found to have high diagnostic performance, with AUC values higher than 0.7 in the four datasets. Therefore, we conclude that these hub-shared genes may serve as novel diagnostic biomarkers and therapeutic targets for sepsis and HF.
During sepsis, microbial infections or necrotic tissues can release harmful substances, leading to excessive activation of immune cells (Xu et al. 2020). Indeed, various immune cells, such as neutrophils and macrophages, are involved in the pathogenesis of sepsis (Kumar 2019). Reinhart et al. (2012) demonstrated that immunological biomarkers can be used to predict the outcome of sepsis. In addition, immune cells are implicated in various cardiovascular diseases, including HF (Adamo et al. 2020), and these immune cells have been used as therapeutic targets for HF (Li et al. 2021). To explore the regulatory mechanism of hub-shared genes, we explored the correlation between hub-shared genes and immune cell infiltration in two diseases in this study and found a significantly negative correlation between RRS1 and M0 macrophages and between IMP4 and plasma cells in the two diseases. These data suggest that RRS1 and IMP4 may participate in the pathogenesis of sepsis and HF by regulating M0 macrophages and plasma cells, respectively. RRS1 and IMP4 are potential immunological biomarkers to predict the risk of the two diseases.
However, this study was performed based on pure bioinformatics analysis, without experimental validations. Thus, more experimental exploration and clinical trials are needed to validate the biological functions of the hub-shared genes as well as their efficacy as diagnostic biomarkers or targets for sepsis and HF.
In conclusion, our findings reveal that four genes, RRS1, IMP4, RPLP0, and NOP16, may be key common regulators in sepsis and HF, which may facilitate precise diagnosis and treatment for the two diseases, especially septic HF.