Progression of Thoracic Aortic Dissection Is Aggravated by the hsa_circ_0007386/miR-1271-5P/IGF1R/AKT Axis via Induction of Arterial Smooth Muscle Cell Apoptosis.

BACKGROUND

The molecular mechanisms associated with thoracic aortic dissection (TAD) remain poorly understood. A comprehensive high-throughput sequencing-based analysis of the circRNA-miRNA-mRNA competitive endogenous RNA (ceRNA) regulatory network in TAD has not been conducted. The purpose of this study is to identify and verify the key ceRNA networks which may have crucial biological functions in the pathogenesis of TAD.

METHODS

Gene expression profiles of the GSE97745, GSE98770, and GSE52093 datasets were acquired from the Gene Expression Omnibus (GEO) database. Differentially expressed genes (DEGs) were identified using the GEO2R tools. Protein-protein interaction (PPI) networks of the hub genes were constructed using STRING; the hub genes and modules were identified by MCODE and CytoHubba plugins of the Cytoscape. We analyzed the hub genes using Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis. The functions of these hub genes were assessed using Cytoscape software. Our data-along with data from GSE97745, GSE98770, and GSE52093-were used to verify the findings.

RESULTS

Upon combined biological prediction, a total of 11 ce-circRNAs, 11 ce-miRNAs, and 26 ce-mRNAs were screened to construct a circRNA-miRNA-mRNA ceRNA network. PPI network and module analysis identified four hub nodes, including IGF1R, JAK2, CSF1, and GAB1. Genes associated with the Ras and PI3K-Akt signaling pathways were clustered in the four hub node modules in TAD. The node degrees were most significant for IGF1R, which were also the most significant in the two modules (up module and hub module). IGF1R was selected as a key gene, and the hsa_circ_0007386/miR-1271-5P/IGF1R/AKT regulatory axis was established. The relative expression levels of the regulatory axis members were confirmed by RT-PCR in 12 samples, including TAD tissues and normal tissues. Downregulation of IGF1R expression in smooth muscle cells (SMCs) was found to induce apoptosis by regulating the AKT levels. In addition, IGF1R showed high diagnostic efficacy in both AD tissue and blood samples.

CONCLUSIONS

The hsa_circ_0007386/miR-1271-5P/IGF1R/AKT axis may aggravate the progression of TAD by inducing VSMCs apoptosis. CeRNA networks could provide new insights into the underlying molecular mechanisms of TAD. In addition, IGF1R showed high diagnostic efficacy in both tissue and plasma samples in TAD, which can be considered as a diagnostic marker for TAD.