title: Ablation of the transcription factor Nrf2 promotes ischemia-induced neovascularization by enhancing the inflammatory response.
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.
  
  
  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-alpha, cyclooxygenase 2, and angiogenic factors in the ischemic hindlimb was also greater for Nrf2(-/-) mice than for wild-type mice.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Human Functional Genomics, Life Science Research Center, Mie University, 1577 Kurimamachiya-cho, Tsu 514-8507, Japan. saho@gene.mie-u.ac.jp
authors.forename: Sahoko
authors.initials: S
authors.lastname: Ichihara
authors.forename: Yoshiji
authors.initials: Y
authors.lastname: Yamada
authors.forename: Fang
authors.initials: F
authors.lastname: Liu
authors.forename: Toyoaki
authors.initials: T
authors.lastname: Murohara
authors.forename: Ken
authors.initials: K
authors.lastname: Itoh
authors.forename: Masayuki
authors.initials: M
authors.lastname: Yamamoto
authors.forename: Gaku
authors.initials: G
authors.lastname: Ichihara
mesh_terms: D000111:Acetylcysteine / Q000494:pharmacology; D042501:Angiogenic Proteins / Q000378:metabolism; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D002196:Capillaries / Q000378:metabolism / Q000503:physiopathology; D015815:Cell Adhesion Molecules / Q000378:metabolism; D018932:Chemokine CCL2 / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000378:metabolism; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000378:metabolism; D005263:Femoral Artery / Q000601:surgery; D005978:Glutathione / Q000378:metabolism; D051547:Heme Oxygenase-1 / Q000378:metabolism; D006614:Hindlimb; D007249:Inflammation / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D018836:Inflammation Mediators / Q000378:metabolism; D007511:Ischemia / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D017078:Laser-Doppler Flowmetry; D008026:Ligation; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018482:Muscle, Skeletal / Q000098:blood supply* / Q000187:drug effects / Q000378:metabolism*; D051267:NF-E2-Related Factor 2 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D018919:Neovascularization, Physiologic / Q000187:drug effects / Q000235:genetics; D018384:Oxidative Stress; D054464:Peroxiredoxins / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D012039:Regional Blood Flow; D013481:Superoxides / Q000378:metabolism; D013879:Thioredoxins / Q000378:metabolism; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D042501:Angiogenic Proteins; D000975:Antioxidants; C491768:Ccl2 protein, mouse; D015815:Cell Adhesion Molecules; D018932:Chemokine CCL2; D018836:Inflammation Mediators; D008565:Membrane Proteins; D051267:NF-E2-Related Factor 2; C495636:Nfe2l2 protein, mouse; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; C515559:Txn1 protein, mouse; D013481:Superoxides; D013879:Thioredoxins; D054464:Peroxiredoxins; C489899:Prdx1 protein, mouse; D051547:Heme Oxygenase-1; C496542:Hmox1 protein, mouse; C077623:Ptgs2 protein, mouse; D051546:Cyclooxygenase 2; D005978:Glutathione; D000111:Acetylcysteine