IRF6 induces endothelial dysfunction through the transcriptional activation of NDRG1 and aggravates low shear...

Atherosclerosis (AS), a chronic inflammatory disorder initiated by vascular endothelial dysfunction (ED), is prominently triggered by hemodynamic low-shear stress (LSS). Interferon regulatory factor 6 (IRF6) is a transcription factor that regulates the inflammatory response following injury. In this work, the LSS-induced AS model was induced by the partial ligation of the left carotid artery in high-fat diet-fed ApoE^-/- mice. After four weeks of feeding, AS mice exhibited higher IRF6 expression and more severe lesions than sham mice. IRF6 suppression alleviated ED, inflammatory response, and oxidative stress in LSS-induced AS mice. In LSS-treated human aortic endothelial cells (HAECs), IRF6 was also highly expressed. Inhibition of IRF6 reduced the expression of pro-inflammatory adhesion molecules and the adhesion of THP-1 cells to HAECs. Mechanistically, IRF6 transcriptionally upregulated NDRG1. NDRG1 upregulation reversed the beneficial effect of IRF6 knockdown. Overall, IRF6 induces ED through the transcriptional activation of NDRG1, aggravating LSS-mediated AS progression.