title: Redox-sensitive transcription factor Nrf2 regulates vascular smooth muscle cell migration and neointimal hyperplasia.
abstract: OBJECTIVE
  Reactive oxygen species are important mediators for platelet-derived growth factor (PDGF) signaling in vascular smooth muscle cells, whereas excess reactive oxygen species-induced oxidative stress contributes to the development and progression of vascular diseases, such as atherosclerosis. Activation of the redox-sensitive transcription factor, nuclear factor erythroid 2-related factor 2 (Nrf2), is pivotal in cellular defense against oxidative stress by transcriptional upregulation of antioxidant proteins. This study aimed to elucidate the role of Nrf2 in PDGF-mediated vascular smooth muscle cell migration and neointimal hyperplasia.
  
  
  RESULTS
  PDGF promoted nuclear translocation of Nrf2, followed by the induction of target genes, including NAD(P)H:quinone oxidoreductase-1, heme oxygenase-1, and thioredoxin-1. Nrf2 depletion by small interfering RNA enhanced PDGF-promoted Rac1 activation and reactive oxygen species production and persistently phosphorylated downstream extracellular signal-regulated kinase-1/2. Nrf2 depletion enhanced vascular smooth muscle cell migration in response to PDGF and wound scratch. In vivo, Nrf2-deficient mice showed enhanced neointimal hyperplasia in a wire injury model.
  
  
  CONCLUSIONS
  These findings suggest that the Nrf2 system is important for PDGF-stimulated vascular smooth muscle cell migration by regulating reactive oxygen species elimination, which may contribute to neointimal hyperplasia after vascular injury. Our findings provide insight into the Nrf2 system as a novel therapeutic target for vascular remodeling and atherosclerosis.
authors: Division of Toxicology, Department of Pharmacology, Toxicology and Therapeutics, Showa University School of Pharmacy, 1-5-8 Hatanodai, Shinagawa-ku, Tokyo 142-8555, Japan. ashino@pharm.showa-u.ac.jp
authors: Takashi
authors: T
authors: Ashino
authors: Masayuki
authors: M
authors: Yamamoto
authors: Takemi
authors: T
authors: Yoshida
authors: Satoshi
authors: S
authors: Numazawa
mesh_terms: D021581:Active Transport, Cell Nucleus; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D000077214:Becaplermin; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D004195:Disease Models, Animal; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005263:Femoral Artery / Q000293:injuries / Q000378:metabolism / Q000473:pathology; D006419:Heme Oxygenase (Decyclizing) / Q000378:metabolism; D006965:Hyperplasia; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000293:injuries / Q000378:metabolism* / Q000473:pathology; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000378:metabolism; D051267:NF-E2-Related Factor 2 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D058426:Neointima; D010084:Oxidation-Reduction; D010766:Phosphorylation; D020574:Proto-Oncogene Proteins c-sis / Q000378:metabolism; D034622:RNA Interference; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction; D013879:Thioredoxins / Q000378:metabolism; D013997:Time Factors; D014162:Transfection; D015854:Up-Regulation; D057772:Vascular System Injuries / Q000235:genetics / Q000378:metabolism* / Q000473:pathology
chemical_list: D000975:Antioxidants; D051267:NF-E2-Related Factor 2; C495636:Nfe2l2 protein, mouse; C495637:Nfe2l2 protein, rat; D020574:Proto-Oncogene Proteins c-sis; D017382:Reactive Oxygen Species; C495697:Txn1 protein, rat; D000077214:Becaplermin; D013879:Thioredoxins; D006419:Heme Oxygenase (Decyclizing); C491523:Hmox1 protein, rat; D016660:NAD(P)H Dehydrogenase (Quinone); C507703:NQO1 protein, rat; D048049:Extracellular Signal-Regulated MAP Kinases