title: Nox4 is a protective reactive oxygen species generating vascular NADPH oxidase.
abstract: BACKGROUND
  The function of Nox4, a source of vascular H(2)O(2), is unknown. Other Nox proteins were identified as mediators of endothelial dysfunction.
  
  
  OBJECTIVE
  We determined the function of Nox4 in situations of increased stress induced by ischemia or angiotensin II with global and tamoxifen-inducible Nox4(-/-) mice.
  
  
  RESULTS
  Nox4 was highly expressed in the endothelium and contributed to H(2)O(2) formation. Nox4(-/-) mice exhibited attenuated angiogenesis (femoral artery ligation) and PEG-catalase treatment in control mice had a similar effect. Tube formation in cultured Nox4(-/-) lung endothelial cells (LECs) was attenuated and restored by low concentrations of H(2)O(2,) whereas PEG-catalase attenuated tube formation in control LECs. Angiotensin II infusion was used as a model of oxidative stress. Compared to wild-type, aortas from inducible Nox4-deficient animals had development of increased inflammation, media hypertrophy, and endothelial dysfunction. Mechanistically, loss of Nox4 resulted in reduction of endothelial nitric oxide synthase expression, nitric oxide production, and heme oxygenase-1 (HO-1) expression, which was associated with apoptosis and inflammatory activation. HO-1 expression is controlled by Nrf-2. Accordingly, Nox4-deficient LECs exhibited reduced Nrf-2 protein level and deletion of Nox4 reduced Nrf-2 reporter gene activity. In vivo treatment with hemin, an inducer of HO-1, blocked the vascular hypertrophy induced by Nox4 deletion in the angiotensin II infusion model and carbon monoxide, the product of HO-1, blocked the Nox4-deletion-induced apoptosis in LECs.
  
  
  CONCLUSIONS
  Endogenous Nox4 protects the vasculature during ischemic or inflammatory stress. Different from Nox1 and Nox2, this particular NADPH oxidase therefore may have a protective vascular function.
authors.affiliation: Institut für Kardiovaskuläre Physiologie, Goethe-Universität, Frankfurt, Germany. schroeder@vrc.uni-frankfurt.de
authors.forename: Katrin
authors.initials: K
authors.lastname: Schröder
authors.forename: Min
authors.initials: M
authors.lastname: Zhang
authors.forename: Sebastian
authors.initials: S
authors.lastname: Benkhoff
authors.forename: Anja
authors.initials: A
authors.lastname: Mieth
authors.forename: Rainer
authors.initials: R
authors.lastname: Pliquett
authors.forename: Judith
authors.initials: J
authors.lastname: Kosowski
authors.forename: Christoph
authors.initials: C
authors.lastname: Kruse
authors.forename: Peter
authors.initials: P
authors.lastname: Luedike
authors.forename: U Ruth
authors.initials: UR
authors.lastname: Michaelis
authors.forename: Norbert
authors.initials: N
authors.lastname: Weissmann
authors.forename: Stefanie
authors.initials: S
authors.lastname: Dimmeler
authors.forename: Ajay M
authors.initials: AM
authors.lastname: Shah
authors.forename: Ralf P
authors.initials: RP
authors.lastname: Brandes
mesh_terms: D000804:Angiotensin II; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D017209:Apoptosis; D001880:Boranes / Q000378:metabolism / Q000494:pharmacology; D002245:Carbon Dioxide / Q000378:metabolism; D002254:Carbonates / Q000378:metabolism / Q000494:pharmacology; D002374:Catalase / Q000494:pharmacology; D002478:Cells, Cultured; D019610:Cytoprotection; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology; D051547:Heme Oxygenase-1 / Q000378:metabolism; D006427:Hemin / Q000494:pharmacology; D061307:Human Umbilical Vein Endothelial Cells / Q000201:enzymology; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism*; D006973:Hypertension / Q000139:chemically induced / Q000201:enzymology* / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D006984:Hypertrophy; D007511:Ischemia / Q000201:enzymology* / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D008168:Lung / Q000098:blood supply*; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018482:Muscle, Skeletal / Q000098:blood supply*; D009247:NADH, NADPH Oxidoreductases / Q000172:deficiency / Q000235:genetics; D000074624:NADPH Oxidase 1; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D051267:NF-E2-Related Factor 2 / Q000235:genetics; D018919:Neovascularization, Physiologic; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D009942:Organometallic Compounds / Q000378:metabolism / Q000494:pharmacology; D018384:Oxidative Stress / Q000187:drug effects; D011092:Polyethylene Glycols / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D013997:Time Factors; D014162:Transfection
chemical_list: D000975:Antioxidants; D001880:Boranes; D002254:Carbonates; D008565:Membrane Proteins; D051267:NF-E2-Related Factor 2; D009942:Organometallic Compounds; D012333:RNA, Messenger; C070295:catalase-polyethylene glycol; C503854:sodium boranocarbonate; C447082:tricarbonyldichlororuthenium (II) dimer; D000804:Angiotensin II; D002245:Carbon Dioxide; D011092:Polyethylene Glycols; D006427:Hemin; D006861:Hydrogen Peroxide; D002374:Catalase; D052250:Nitric Oxide Synthase Type III; C496315:Nos3 protein, mouse; D051547:Heme Oxygenase-1; C496542:Hmox1 protein, mouse; D009247:NADH, NADPH Oxidoreductases; D000074624:NADPH Oxidase 1; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases; C000614711:NOX1 protein, mouse; C498910:NOX4 protein, human; C422943:Nox4 protein, mouse