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. <i>In vitro</i>, 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. <i>In vivo</i>, 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 <i>in vivo</i>. These findings demonstrate that these electrophilic activators suppress restenosis by stabilizing VSMC phenotype via strictly Nrf2-dependent signaling.