Role of NADPH oxidase in endothelial ischemia/reperfusion injury in humans.
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.
Loukogeorgakis
Stavros P
SP
Institute of Child Health, University College London, UK. s.loukogeorgakis@ich.ucl.ac.uk
van den Berg
Merlijn J
MJ
Sofat
Reecha
R
Nitsch
Dorothea
D
Charakida
Marietta
M
Haiyee
Bu'Hussein
B
de Groot
Eric
E
MacAllister
Raymond J
RJ
Kuijpers
Taco W
TW
Deanfield
John E
JE
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
D008562:Membrane Glycoproteins; D017382:Reactive Oxygen Species; C056558:CYBB protein, human; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases; C060505:neutrophil cytosolic factor 1