Convergent Transcriptional Regulation of Endothelial Dysfunction by Oxidative Stress and Inflammatory Stimulation: A Multi-Dataset Gene Expression Meta-Analysis
DOI:
https://doi.org/10.58445/rars.4073Keywords:
vascular inflammatory disease, NFKB1, ICAM1, SELE, endothelial cells, vascular endotheliumAbstract
Endothelial cell activation is both an early and critical event in atherosclerosis and vascular inflammatory disease, which is caused by reactive oxygen species (ROS) and pro-inflammatory cytokines. Nevertheless, it is still unclear if these two different stimuli can activate the same program of gene expression related to the NF-κB signalling and leukocyte-adhesion pathways.
This study used 9 publicly available GEO transcriptomic datasets from human endothelial cells that were exposed to oxidative stress (H₂O₂ and other related redox issues) or inflammatory stimulation (TNF-α, IL-1β, LPS), across 154 samples (24 control, 130 stimulated). Following log₂ transformation and per-dataset z-score standardisation to normalize the data, differences in gene expression were observed via an ordinary least squares (OLS) model with dummy variables to account for batch effects. Pathway enrichment was evaluated using over-representation analysis (ORA) and pre-ranked gene set enrichment analysis (GSEA).
A total of 1864 genes showed significant changes in gene expression, of which 1075 genes were upregulated, and 789 genes were downregulated. Of the four specified hub genes, NFKB1, ICAM1, and SELE were significantly upregulated with FDR values of 0.007, 0.011, and 0.018, respectively. For VCAM1, the effect size was consistently positive, but it did not reach significance (FDR value of 0.060). GSEA identified the most positively enriched pathways were TNF signalling (NES = 2.83, FDR q < 0.001), NIK/NF-κB signalling (NES = 2.41, FDR q< 0.001), and cytokine-cytokine receptor interaction (NES = 2.89, FDR q< 0.001).
Human endothelial cells that are subjected to oxidative and inflammatory stimulation produce a convergent gene expression program, where NF-κB activation and subsequent upregulation of leukocyte-adhesion molecules are observed. In both stimulus types, hub genes NFKB1, ICAM1, and SELE act as reproducible convergent hub genes, supporting that they represent possible therapeutic targets in vascular inflammatory disease.
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