Transcriptome Analyses Identify a Pyroptosis-Related Transcription Factor-microRNA-mRNA Regulatory Network for Vascular Dementia

Abstract

Background: Vascular dementia (VaD) is a kind of cerebrovascular diseases characterized by decreased cognitive function. No effective treatments have been approved for the treatment of VaD. Accumulative evidence reveals that pyroptosis plays a key role in mediating VaD. Therefore, this study aimed to identify pyroptosis-linked hub genes by using bioinformatics analysis and construct a regulatory network among transcription factors (TFs), microRNAs (miRNAs), and mRNAs for VaD. Methods: Differentially expressed genes (DEGs) in the frontal cortex between VaD and control samples were identified. Several analyses were performed, including functional enrichment, protein-protein interaction (PPI), miRNA-target gene interaction, transcription factor-microRNA (TF-miRNA) interaction, and drug-hub gene interaction. The goal was to obtain pyroptosis-related hub genes and create a TF-miRNA-mRNA regulatory network for VaD. Results: We identified 27 DEGs related to pyroptosis, nine of which were considered as pyroptosis-related hub genes. These hub genes were nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3), TLR2, CASP1, heat shock protein 90 kDa alpha family class A member 1 (HSP90AA1), VEGFA, AIM2, LY96, CEBPB, and BTK. In our TF-miRNA-mRNA regulatory network, two hub genes (vascular endothelial growth factor-A (VEGFA) and heat shock protein 90 kDa alpha family class A member 1 (HSP90AA1)), four miRNAs (miR-1304-3p, miR-1293, miR-191-5p, and miR-5193), and five TFs (Early Growth Response Protein 1 (EGR1), runt-related transcription factor-1 (RUNX1), SPI1, PHD finger protein 8 (PHF8), and CCAAT/enhancer binding protein beta (CEBPB)) were identified as potential biomarkers for VaD. The expression levels of these key target genes, miRNAs, and TFs were verified using an oxygen-glucose deprivation (OGD)-induced SH-SY5Y cell model. The drug-target gene interaction analysis revealed that three drugs (tanespimycin, bevacizumab, and aflibercept) targeting HSP90AA1 and VEGFA could be potential drugs for VaD treatment. Conclusions: This study built a pyroptosis-related regulatory network among TFs, miRNAs, and target genes for VaD. The results of this study might assist with clarifying the new molecular mechanisms of VaD. Additionally, HSP90AA1 and VEGFA were identified as potential biomarkers or therapeutic targets for VaD treatment.