Comprehensive Analysis of Endoplasmic Reticulum Stress in Intracranial Aneurysm

Background: Aberrant endoplasmic reticulum stress (ERS) plays an important role in multiple cardiovascular diseases. However, their implication in intracranial aneurysms (IAs) remains unclear. We designed this study to explore the general expression pattern and potential functions of ERS in IAs.

Methods: Five Gene Expression Omnibus (GEO) microarray datasets were used as the training cohorts, and 3 GEO RNA sequencing (RNA-seq) datasets were used as the validating cohorts. Differentially expressed genes (DEGs), functional enrichment, Lasso regression, logistic regression, ROC analysis, immune cell profiling, vascular smooth muscle cell (VSMC) phenotyping, weighted gene coexpression network analysis (WGCNA), and protein-protein interaction (PPI) analysis were applied to investigate the role of ERS in IA. Finally, we predicted the upstream transcription factor (TF)/miRNA and potential drugs targeting ERS.

Results: Significant DEGs were majorly associated with ERS, autophagy, and metabolism. Eight-gene ERS signature and IRE1 pathway were identified during the IA formation. WGCNA showed that ERS was highly associated with a VSMC synthesis phenotype. Next, ERS-VSMC-metabolism-autophagy PPI and ERS-TF-miRNA networks were constructed. Finally, we predicted 9 potential drugs targeting ERS in IAs.

Conclusion: ERS is involved in IA formation. Upstream and downstream regulatory networks for ERS were identified in IAs. Novel potential drugs targeting ERS were also proposed, which may delay IA formation and progress.