Inhibition of smooth muscle phenotypic modulation by bardoxolone methyl, omaveloxolone, and cinnamaldehyde is Nrf-2 dependent.

Neointimal hyperplasia (NH) is a primary cause of arterial restenosis following angioplasty, driven by oxidative stress and vascular smooth muscle cell (VSMC) phenotypic modulation. This study investigated whether the class I electrophilic Nrf2 activators Bardoxolone methyl (BAR), Omaveloxolone (OMV), and Cinnamaldehyde (CA) could suppress NH through Nrf2-dependent mechanisms. Using VSCM that were Nrf2 wild-type (WT), knockout (KO), and rescued by nrf2 lentiviral transduction, we assessed the effects of these activators on PDGF-induced proliferation, migration, and phenotypic modulation. Additionally, we utilized a rat carotid artery balloon injury model with periadventitial drug delivery and light-sheet fluorescence microscopy to evaluate neointimal formation. In vitro, BAR, OMV, and CA upregulated the antioxidant enzymes HO-1 and NQO1, inhibited cell migration and proliferation, and preserved contractile markers (calponin and transgelin) in WT VSMC, but showed no effect in KO cells. Lentiviral-mediated nrf2 transduction rescued the phenotype. In vivo, treatment with CA significantly reduced neointimal volume and stenosis in WT rats, but failed to inhibit hyperplasia in Nrf2 KO rats. Aditionally, BAR also showed marked inhibition of hyperplasia in vivo. These findings demonstrate that these electrophilic activators suppress restenosis by stabilizing VSMC phenotype via strictly Nrf2-dependent signaling.