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bioRxiv · 10.1101/2023.05.02.539148

Syndecan-4 is the Key Proteoglycan Mediating LPS-induced Sepsis-associated Lung Injury

Zhu, Z.·Ling, X.·Zhou, H.·Xie, J.
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Abstract

The occurrence of acute sepsis-associated lung injury (ALI) is closely related to vascular endothelial cell dysfunction, but the exact isoform of the functional syndecans (SDCs) located in the inner endothelial membrane of blood vessels and involved in regulating inflammation is not clear. The present study aimed to clarify whether SDC2 and/or 4 is involved in the inflammation process.Using the Gene Expression Omnibus (GEO) database, differentially expressed genes (DEGs) were extracted and analyzed. A bioinformatic analysis was conducted using R language, gene ontology (GO), and the Kyoto Encyclopedia of Genes and Genomes (KEGG) with the aim of predicting SDC2 and 4 expression levels. Subsequently, the expression profiles of these two proteins were examined after construction of a sepsis-associated ALI mmodel was constructed in both human lung vascular endothelial cells (HLVEC) and animal models under inflammatory conditions. Eventually, the transcription factors (TF) of SDC2/4 were predicted based on the available dataset, and their involvement in septic inflammation was indirectly assessed. The GSE 5883 microarray gene-chip data profile was found to be suitable for analyzing lipopolysaccharide (LPS)-induced endothelial inflammatory injury. After analyzing the DEGs, 224 and 102 genes were found to be up- and down-regulated, respectively. All DEGs were involved in modulating receptor ligand and signaling receptor activator activities, cytokine receptor binding in biological processes, such as responses to lipopolysaccharide (LPS) and molecules from bacterial origins, positive regulation of cell adhesion, and other functions. In the case of localization of cellular components, most DEGs were enriched in cytoplasmic ribonucleoprotein granules, transcription regulator complex, and membrane rafts and were involved in the tumor necrosis factor (TNF) signaling and cytokine receptor interaction pathways. When compared with the control group, SDC4 gene expression in the LPS group increased by 4.5-fold, and comparable results were found in terms of SDC2 gene expression. From an experimental aspect, SDC4 was found to be markedly up-regulated with respect to mRNA and protein expression levels in response to inflammatory injury; moreover, down-regulation of SDC4 could severely exacerbate inflammatory responses either in in vivo or in vitro models. Altogether, SDC4, rather than SDC2, was found to be involved in LPS-induced sepsis-associated ALI.

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Zhu, Z., Ling, X., Zhou, H., Xie, J.. 2023-05-02. Syndecan-4 is the Key Proteoglycan Mediating LPS-induced Sepsis-associated Lung Injury. https://doi.org/10.1101/2023.05.02.539148

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