Regulatory Master Genes Identification and Drug Repositioning by Integrative mRNA-miRNA Network Analysis for Acute Type A Aortic Dissection

Abstract

Acute type A aortic dissection (ATAAD) is a life-threatening disease. The understanding of its pathogenesis and treatment approaches remains unclear. In the present work, differentially expressed genes (DEGs) from two ATAAD datasets GSE52093 and GSE98770 were filtered. Transcription factor TEAD4 was predicted as a key modulator in protein-protein interaction (PPI) network. Weighted correlation network analysis (WGCNA) identified five modules in GSE52093 and four modules in GSE98770 were highly correlated with ATAAD. 71 consensus DEGs of highly correlated modules were defined and functionally annotated. L1000CDS2 was executed to predict drug for drug repositioning in ATAAD treatment. Eight compounds were filtered as potential drugs. Integrative analysis revealed the interaction network of five differentially expressed miRNA and 16 targeted DEGs. Finally, master DEGs were validated in human ATAAD samples and AD cell model in vitro. TIMP3 and SORBS1 were downregulated in ATAAD samples and AD cell model, while PRUNE2 only decreased in vitro. Calcium channel blocker and glucocorticoid receptor agonist might be potential drugs for ATAAD. The present study offers potential targets and underlying molecular mechanisms ATAAD pathogenesis, prevention and drug discovery.