抄録
Platelet-derived growth factor (PDGF) is a potent stimulator of vascular smooth muscle cell (VSMC) migration, which plays a key role in the recovery from vascular injury. Reactive oxygen species (ROS) are important mediators for PDGF signaling in VSMCs, whereas excess ROS-induced oxidative stress contributes to the development and the progression of vascular diseases such as atherosclerosis. Activation of the redox-sensitive transcription factor Nrf2 plays a pivotal role in the cellular defense against oxidative stress via transcriptional upregulation of antioxidant stress proteins; however, the role of Nrf2 in PDGF-mediated VSMC migration and neointimal formation has not been established. Here we show that PDGF (25 ng/mL) promotes ROS production (133%) through Rac1 activation (227%), thereby evoking nuclear translocation of Nrf2 in VSMCs isolated from the thoracic aorta of Sprague-Dawley rats. In addition, real-time PCR analysis showed that PDGF stimulation induces expression of Nrf2-target genes, including NAD(P)H:quinone oxidoreductase-1 (287%), heme oxygenase-1 (678%) and thioredoxin-1 (213%). Depletion of Nrf2 with siRNA enhanced PDGF-promoted Rac1 activation (174%) and ROS production (150%), and continuously phosphorylated the downstream kinase ERK but not p38 and Akt. Functionally, Nrf2 depletion enhanced VSMC migration in response to PDGF (182%) and wound scratch (160%). In vivo, Nrf2 deficient mice showed enhanced neointimal formation in a wire-injury model. In summary, Nrf2 system plays an important role in PDGF-stimulated VSMC migration via regulating ROS elimination, which may contributes to neointimal formation after vascular injury. Our findings provide insight into Nrf2 system as a novel therapeutic target for vascular remodeling and atherosclerosis.
