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Oxidative stress and abnormal proliferation and migration of vascular smooth muscle cells (VSMCs) influence atherosclerosis formation and development. Oxidative stress significantly influences the abnormal proliferation and migration of VSMCs, and nuclear factor erythroid 2-related factor 2 (Nrf2) is a major antioxidant factor. However, the precise function of Nrf2 in the regulation of abnormal proliferation and migration of VSMCs and atherosclerosis is unclear. We investigated the proliferation and migration of VSMCs in atherosclerosis in male Apoe −/− and Apoe −/− Nrf2 −/− mice fed a high-fat diet for 12 weeks. In cultured mouse VSMCs, we studied the effect of Nrf2 on ox-LDL-stimulated proliferation and migration by using siRNA treatment to silence Nrf2. We then performed dual luciferase reporter and immunoprecipitation assays to study the interaction between Nrf2 and the promoter sequence of lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1). Our results demonstrate that Nrf2 expression levels were increased in the aorta and VSMCs of mice in the atherosclerosis model group compared with the control group. We also provide evidence that Nrf2 deficiency attenuated atherosclerotic plaque burden, diminished proliferation, and migration of VSMCs but enhanced VSMC-specific marker gene expression in vitro and in vivo. This is related to Nrf2 binding to the promoter sequence of LOX-1. Furthermore, Nrf2 downregulation contributes to restrain both transcriptional and translational activities of LOX-1. Together, our data indicate that Nrf2 insufficiency is linked to attenuation of atherosclerosis, and could diminish the pathological process by blunting LOX-1-mediated proliferation and migration of VSMCs. [Display omitted] • Nrf2 drives atherosclerotic plaque formation. • Ox-LDL augments the expression of Nrf2 in mouse vascular smooth muscle cells (VSMCs). • Nrf2 induces proliferation and migration of VSMCs in Apoe −/− mice and in vitro. • Nrf2 deficiency diminishes LOX-1 activity and the oxidative stress level of VSMCs in vitro and in vivo. • Nrf2 binds LOX-1 promoter and increases its expression. [ABSTRACT FROM AUTHOR]