Redox-sensitive transcription factor Nrf2 regulates vascular smooth muscle cell migration and neointimal hyperplasia

Takashi Ashino, Masayuki Yamamoto, Takemi Yoshida, Satoshi Numazawa

Research output: Contribution to journalArticlepeer-review

53 Citations (Scopus)

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. APPROACH AND 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. CONCLUSION: 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.

Original languageEnglish
Pages (from-to)760-768
Number of pages9
JournalArteriosclerosis, thrombosis, and vascular biology
Volume33
Issue number4
DOIs
Publication statusPublished - 2013 Apr

Keywords

  • Nrf2
  • cell migration
  • neointimal hyperplasia
  • platelet-derived growth factor
  • vascular smooth muscle cell

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

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