DDX17 deficiency inhibits the proliferation and migration of vascular smooth muscle cells by inhibiting RHEB/mTORC1-mediated glycolysis and oxidative stress.

As an RNA-binding protein, DEAD-box RNA helicase 17 (DDX17) plays a critical role in influencing gene expression and participates in the proliferation and migration of several cell lines. The current study aims to investigate the role of DDX17 in vascular smooth muscle cell (VSMC) proliferation and migration and vascular intimal hyperplasia. DDX17 expression was upregulated in injured mouse arteries and platelet derived growth factor (PDGF)-BB-treated VSMCs. An adeno-associated virus serotype 9 vector carrying Ddx17 short hairpin RNA (shDdx17) was used to silence DDX17 expression in vivo. DDX17 silencing significantly ameliorated injury-induced mouse vascular intimal hyperplasia. In vitro, the recombinant lentivirus carrying Ddx17 shRNA (Len-Ddx17i) was used to inhibition DDX17 expression in VSMCs. DDX17 deficiency inhibited PDGF-BB-induced phenotypic switching of VSMCs. Bioinformatics analysis revealed that DDX17 expression is closely related to glucose metabolism- and oxidative stress-associated pathways. Next, we found that glycolysis and oxidative stress were both attenuated by DDX17 ablation in VSMCs. Mechanically, reduced ras homolog enriched in brain (RHEB) expression and decreased mammalian target of rapamycin complex 1 (mTORC1) activity were observed after silencing of DDX17 in PDGF-BB-challenged VSMCs. Upregulating RHEB expression or elevating mTORC1 activity abolished the inhibitory effects of DDX17 silencing on PDGF-BB-induced glycolysis, oxidative stress, proliferation, and migration in VSMCs. Furthermore, the decreased mTORC1 activity induced by DDX17 deficiency was also reversed by RHEB overexpression. In conclusion, DDX17 silencing attenuates VSMC proliferation and migration by inhibiting RHEB/mTORC1-mediated glycolysis and oxidative stress, thus suppressing vascular intimal hyperplasia.