Ablation of the transcription factor Nrf2 promotes ischemia-induced neovascularization by enhancing the inflammatory response

Sahoko Ichihara, Yoshiji Yamada, Fang Liu, Toyoaki Murohara, Ken Itoh, Masayuki Yamamoto, Gaku Ichihara

Research output: Contribution to journalArticle

31 Citations (Scopus)

Abstract

Objective: To investigate the potential role of nuclear factor-erythroid 2-related factor 2 (Nrf2) in neovascularization with a murine surgical model of ischemia. Methods and results: The transcription factor Nrf2 protects against oxidative stress by increasing the transcription of genes, including those for several antioxidant enzymes that contain an antioxidant response element. Ischemia was induced by femoral artery ligation in Nrf2-deficient (Nrf2 -/-) and wild-type mice. Ischemia-induced neovascularization was enhanced in Nrf2-/- mice compared with that in wild-type mice. The expression of Nrf2 target genes for heme oxygenase 1 and thioredoxin 1 and the concentration of total glutathione in the ischemic hindlimb were reduced for Nrf2-/- mice compared with wild-type mice. The infiltration of inflammatory cells and the abundance of adhesion molecule mRNA were greater in the ischemic hindlimb of Nrf2-/- mice than in wild-type mice. The expression of monocyte chemoattractant protein-1, tumor necrosis factor-α, cyclooxygenase 2, and angiogenic factors in the ischemic hindlimb was also greater for Nrf2-/- mice than for wild-type mice. Conclusion: The ablation of Nrf2 promoted ischemia-induced neovascularization. This effect likely resulted from impaired antioxidant defense and increased accumulation of reactive oxygen species in endothelial cells; consequently, there was an enhanced inflammatory response.

Original languageEnglish
Pages (from-to)1553-1561
Number of pages9
JournalArteriosclerosis, thrombosis, and vascular biology
Volume30
Issue number8
DOIs
Publication statusPublished - 2010 Aug 1

Keywords

  • endothelial cells
  • inflammation
  • ischemia
  • neovascularization
  • peripheral vascular disease

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

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