Involvement of DHX9/YB-1 complex induced alternative splicing of Krüppel-like factor 5 mRNA in phenotypic transformation of vascular smooth muscle cells

Abstract

Phenotypic transformation of vascular smooth muscle cells is a key phenomenon in the development of aortic dissection disease. However, the molecular mechanisms underlying this phenomenon have not been fully understood. We used β-BAPN combined with ANG II treatment to establish a disease model of acute aortic dissection (AAD) in mice. We first examined the gene expression profile of aortic tissue in mice with AAD using a gene chip, followed by confirmation of DExH-box helicase 9 (DHX9) expression using RT-PCR, Western blot, and immunofluorescence analysis. We further developed vascular smooth muscle cell-specific DHX9 conditional knockout mice and conducted differential and functional analysis of gene expression and alternative splicing in mouse vascular smooth muscle cells. Finally, we examined the involvement of DHX9 in Krüppel-like factor 5 ( KLF5) mRNA alternative splicing. Our study reported a significant decrease in the expression of DHX9 in the vascular smooth muscle cells (VSMCs) of mice with AAD. The smooth muscle cell-specific knockout of DHX9 exacerbated the development of AAD and altered the transcriptional level expression of many smooth muscle cell phenotype-related genes. Finally, we reported that DHX9 may induce alternative splicing of KLF5 mRNA by bridging YB-1. These results together suggested a new pathogenic mechanism underlying the development of AAD, and future research of this mechanism may help identify effective therapeutic intervention for AAD.