Abstract 157: Sulfasalazine Inhibits Neointimal Formation Through Induction Of Heme Oxygenase-1 Via Nrf2/ARE and Jnk Signaling
Objective-Sulfasalazine has been used for an anti-inflammatory drug of which mechanism is on debate. Recently, nuclear factor erythroid 2-related factor 2(Nrf2) has been reported to play a major role in cellular defenses in vascular tissue. However, the role of Nrf2 in neointimal growth after balloon angioplasty has not been elucidated. We investigated whether sulfasalazine could inhibit neointimal formation of balloon-injured vessels by modulation of Nrf2.
Methods and Results-Sulfasalazine suppresses PDGF-induced proliferation and cell cycle progression of rat vascular smooth muscle cells (VSMCs) in dose-dependent manner. Sulfasalazine induced heme oxygenase-1 (HO-1) in VSMCs, which was followed by increased expression of p21 protein and cell cycle arrest. HO-1 inhibitor, ZnPP, reversed the cell cycle arrest and p21 induction by sulfasalazine. The underlying mechanism for sulfasalazine to induce HO-1 was through nuclear translocation and activation of Nrf2 and c-jun, which was reversed by N-acetyl cysteine, suggesting that these effects were mediated by reactive oxygen species (ROS). Sulfasalazine-induced HO-1 expression was inhibited by adenovirus encoding dominant-negative mutant form of Nrf2 or c-Jun NH2-terminal kinase (JNK) inhibitor, SP000125. In rat carotid artery balloon injury model, administration of sulfasalazine significantly suppressed proliferation of VSMCs and neointimal formation with induction of HO-1 that associated with nuclear translocation of Nrf2. Gene transfer with adenovirus encoding dominant-negative mutant form of Nrf2 attenuated induction of HO-1 and suppression of neointimal formation in sulfasalazine-treated rats.
Conclusions- Sulfasalazine inhibits VSMCs proliferation by induction of HO-1 through ROS-dependent Nrf2 and JNK signaling, suggesting that sulfasalazine to control ROS signaling and HO-1 expression may be an important therapeutic option to regulate the proliferative vasculopathy.