title: Role of NADPH oxidase in endothelial ischemia/reperfusion injury in humans.
abstract: BACKGROUND
  Reactive oxygen species have been implicated in the pathogenesis of ischemia/reperfusion (IR) injury. Recent studies suggest that NADPH oxidase may be a source of ROS during IR. Using an in vivo model of endothelial IR injury in the arm, we compared the response to IR in healthy volunteers with that in patients with chronic granulomatous disease. These patients have a molecular lesion in a subunit of NADPH oxidase that renders the enzyme inactive.
  
  
  RESULTS
  Flow-mediated dilatation was used to assess endothelial function in patients with X-linked (NOX2) or autosomal (p47) chronic granulomatous disease. IR injury was induced by 20 minutes of upper limb ischemia followed by reperfusion. Flow-mediated dilatation was determined before IR and after 20 minutes of reperfusion. The response to IR in chronic granulomatous disease patients was compared with that in age- and sex-matched healthy control subjects. Flow-mediated dilatation was expressed as mean and compared statistically with mixed linear models. IR caused a significant reduction in flow-mediated dilatation in control subjects (-5.1%; 95% confidence interval, 6.3 to 3.%; P<0.001; n=11). IR had no effect on endothelial function in NOX2-chronic granulomatous disease patients (-0.9; 95% confidence interval, -2.1 to 0.3; P=0.12; n=11). Similarly, IR-induced reduction in flow-mediated dilatation was not observed in p47-chronic granulomatous disease patients (-1.5%; 95% confidence interval, -3.1 to 0.2; P=0.08; n=6) in contrast to healthy control subjects (-6.5%; 95% confidence interval, -8.2 to -4.9%; P<0.001; n=6).
  
  
  CONCLUSIONS
  These data indicate, for the first time in humans in vivo, that reactive oxygen species produced by NADPH oxidase are determinants of endothelial function after IR injury in humans. These findings have implications for the design of strategies to limit clinical IR injury.
authors.affiliation: Institute of Child Health, University College London, UK. s.loukogeorgakis@ich.ucl.ac.uk
authors.forename: Stavros P
authors.initials: SP
authors.lastname: Loukogeorgakis
authors.forename: Merlijn J
authors.initials: MJ
authors.lastname: van den Berg
authors.forename: Reecha
authors.initials: R
authors.lastname: Sofat
authors.forename: Dorothea
authors.initials: D
authors.lastname: Nitsch
authors.forename: Marietta
authors.initials: M
authors.lastname: Charakida
authors.forename: Bu'Hussein
authors.initials: B
authors.lastname: Haiyee
authors.forename: Eric
authors.initials: E
authors.lastname: de Groot
authors.forename: Raymond J
authors.initials: RJ
authors.lastname: MacAllister
authors.forename: Taco W
authors.initials: TW
authors.lastname: Kuijpers
authors.forename: John E
authors.initials: JE
authors.lastname: Deanfield
mesh_terms: D000293:Adolescent; D000328:Adult; D001794:Blood Pressure / Q000502:physiology; D001916:Brachial Artery / Q000503:physiopathology; D016022:Case-Control Studies; D004730:Endothelium, Vascular / Q000503:physiopathology*; D005260:Female; D006105:Granulomatous Disease, Chronic / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology*; D006801:Humans; D008297:Male; D008562:Membrane Glycoproteins / Q000378:metabolism; D008875:Middle Aged; D008954:Models, Biological; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D017382:Reactive Oxygen Species / Q000378:metabolism; D015427:Reperfusion Injury / Q000378:metabolism / Q000503:physiopathology*; D055815:Young Adult
chemical_list: D008562:Membrane Glycoproteins; D017382:Reactive Oxygen Species; C056558:CYBB protein, human; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases; C060505:neutrophil cytosolic factor 1