title: Reduced atherosclerotic burden in subjects with genetically determined low oxidative stress.
abstract: OBJECTIVE
  NADPH oxidase, one of the most important enzymes producing reactive oxidant species, is suggested to play a role in experimental atherosclerosis, but its role in human atherosclerosis is still unclear. We hypothesized that a reduced activity of NADPH oxidase might be linked to a reduced atherosclerotic burden.
  
  
  RESULTS
  Thirty-one women carriers of hereditary deficiency of NOX2, the catalytic subunit of NADPH oxidase, were matched for sex and age with 31 controls and 31 obese women. Flow-mediated dilation and intima-media thickness, 2 surrogate markers of atherosclerosis, serum activity of NOX2, urinary isoprostanes, serum levels of nitrite/nitrate, and platelet production of isoprostanes and nitrite/nitrate were determined. Compared with controls (5.7±3.0% and 0.60±0.11 mm), carriers of NOX2 deficiency had higher flow-mediated dilation (9.2±5.0%; P<0.001) and lower intima-media thickness (0.50±0.11 mm; P=0.002), whereas obese women had lower flow-mediated dilation (3.2±2.1%; P=0.007) and higher intima-media thickness (0.71±0.15 mm; P<0.001). Compared with controls, carriers of NOX2 deficiency had lower urinary isoprostanes (132.6±87.3 versus 82.3±46.0 pg/mg creatinine; P=0.007) and serum NOX2 activity (24.9±19.3 versus 12.8±11.9 pg/mL; P=0.004) and higher serum nitrite/nitrate (23.8±7.6 versus 30.5±6.3 µmol/L; P<0.001), whereas obese women had higher urinary isoprostanes (132.6±87.3 versus 182.2±84.6 pg/mg creatinine; P=0.008) and serum NOX2 activity (24.9±19.3 versus 36.1±18.6 pg/mL; P=0.008) and lower serum nitrite/nitrate (23.8±7.6 versus 12.6±4.2 µmol/L; P<0.001). Flow-mediated dilation correlated with intima-media thickness (r=-0.433; P<0.001), serum NOX2 activity (r=-325; P<0.001), and urinary isoprostanes (r=-0.314; P=0.002). Ex vivo study showed that, compared with controls, platelets from carriers of NOX2 deficiency had lower isoprostanes (P<0.001) and higher nitrite/nitrate (P<0.001), whereas platelets from obese women had higher isoprostanes (P<0.001) and lower nitrite/nitrate (P=0.013).
  
  
  CONCLUSIONS
  The study shows reduced atherosclerotic burden in carriers of NOX2 deficiency, suggesting that oxidative stress generated by this enzymatic pathway is implicated in human atherosclerosis.
authors.affiliation: Clinica Medica I, Sapienza University of Rome, Rome, Italy. francesco.violi@uniroma1.it
authors.forename: Francesco
authors.initials: F
authors.lastname: Violi
authors.forename: Pasquale
authors.initials: P
authors.lastname: Pignatelli
authors.forename: Claudio
authors.initials: C
authors.lastname: Pignata
authors.forename: Alessandro
authors.initials: A
authors.lastname: Plebani
authors.forename: Paolo
authors.initials: P
authors.lastname: Rossi
authors.forename: Valerio
authors.initials: V
authors.lastname: Sanguigni
authors.forename: Roberto
authors.initials: R
authors.lastname: Carnevale
authors.forename: Annarosa
authors.initials: A
authors.lastname: Soresina
authors.forename: Andrea
authors.initials: A
authors.lastname: Finocchi
authors.forename: Emilia
authors.initials: E
authors.lastname: Cirillo
authors.forename: Elisa
authors.initials: E
authors.lastname: Catasca
authors.forename: Francesco
authors.initials: F
authors.lastname: Angelico
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Loffredo
mesh_terms: D000328:Adult; D050197:Atherosclerosis / Q000201:enzymology / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D015415:Biomarkers / Q000097:blood / Q000652:urine; D001916:Brachial Artery / Q000503:physiopathology; D059168:Carotid Intima-Media Thickness; D016022:Case-Control Studies; D016009:Chi-Square Distribution; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D028421:Isoprostanes / Q000097:blood / Q000652:urine; D007558:Italy; D016014:Linear Models; D008562:Membrane Glycoproteins / Q000097:blood / Q000235:genetics*; D008875:Middle Aged; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases / Q000097:blood / Q000235:genetics*; D009566:Nitrates / Q000097:blood; D009573:Nitrites / Q000097:blood; D009765:Obesity / Q000201:enzymology / Q000473:pathology / Q000503:physiopathology; D018384:Oxidative Stress / Q000235:genetics*; D010641:Phenotype; D011237:Predictive Value of Tests; D014664:Vasodilation
chemical_list: D015415:Biomarkers; D028421:Isoprostanes; D008562:Membrane Glycoproteins; D009566:Nitrates; D009573:Nitrites; C056558:CYBB protein, human; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases