title: Coronary artery superoxide production and nox isoform expression in human coronary artery disease.
abstract: BACKGROUND
  Oxidative stress plays important role in the pathogenesis of atherosclerosis and coronary artery disease (CAD). We aimed to determine the sources and selected molecular mechanisms of oxidative stress in CAD.
  
  
  RESULTS
  We examined basal and NAD(P)H oxidase-mediated superoxide (O2*-) production using lucigenin chemiluminescence, ferricytochrome c and dihydroethidium fluorescence in human coronary arteries from 19 CAD and 17 non-CAD patients undergoing heart transplantation. NAD(P)H oxidase subunits and xanthine oxidase expression were measured. Superoxide production was greater in coronary arteries from patients with CAD, even in vessels without overt atherosclerotic plaques, and was doubled within branching points of coronary arteries. Studies using pharmacological inhibitors and specific substrates showed that NAD(P)H oxidases (60%) and xanthine oxidase (25%) are primary sources of O2*- in CAD. Losartan significantly inhibited superoxide production in coronary arteries. NAD(P)H oxidase activity and protein levels of the NADPH oxidase subunits p22phox, p67phox, and p47phox were significantly increased in CAD, as were mRNA levels for p22phox and nox2, and no NAD(P)H oxidase subunit mRNA levels correlated with NAD(P)H oxidase activity in vessels from individual patients. Activity and protein expression of xanthine oxidase were increased in CAD, whereas xanthine dehydrogenase levels were not changed.
  
  
  CONCLUSIONS
  Increased expression and activity of NAD(P)H oxidase subunits and xanthine oxidase, in part mediated through angiotensin II and PKC-dependent pathways, are important mechanisms underlying increased oxidative stress in human coronary artery disease.
authors.affiliation: Department of Cardiovascular Medicine, University of Oxford, John Radcliffe Hospital, United Kingdom. tguzik@emory.edu
authors.forename: Tomasz J
authors.initials: TJ
authors.lastname: Guzik
authors.forename: Jerzy
authors.initials: J
authors.lastname: Sadowski
authors.forename: Bartlomiej
authors.initials: B
authors.lastname: Guzik
authors.forename: Andrew
authors.initials: A
authors.lastname: Jopek
authors.forename: Boguslaw
authors.initials: B
authors.lastname: Kapelak
authors.forename: Piotr
authors.initials: P
authors.lastname: Przybylowski
authors.forename: Karol
authors.initials: K
authors.lastname: Wierzbicki
authors.forename: Ryszard
authors.initials: R
authors.lastname: Korbut
authors.forename: David G
authors.initials: DG
authors.lastname: Harrison
authors.forename: Keith M
authors.initials: KM
authors.lastname: Channon
mesh_terms: D000328:Adult; D000804:Angiotensin II / Q000378:metabolism / Q000494:pharmacology; D003324:Coronary Artery Disease / Q000378:metabolism* / Q000473:pathology; D003331:Coronary Vessels / Q000201:enzymology* / Q000473:pathology; D005260:Female; D006801:Humans; D008297:Male; D026901:Membrane Transport Proteins / Q000378:metabolism*; D008875:Middle Aged; D019255:NADPH Oxidases / Q000378:metabolism*; D018384:Oxidative Stress / Q000502:physiology*; D010750:Phosphoproteins / Q000378:metabolism*; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism; D013481:Superoxides / Q000378:metabolism*; D014662:Vasoconstrictor Agents / Q000378:metabolism / Q000494:pharmacology; D014969:Xanthine Oxidase / Q000378:metabolism
chemical_list: D026901:Membrane Transport Proteins; D010750:Phosphoproteins; D014662:Vasoconstrictor Agents; C079789:neutrophil cytosol factor 67K; D013481:Superoxides; D000804:Angiotensin II; D014969:Xanthine Oxidase; D019255:NADPH Oxidases; C086986:CYBA protein, human; C060505:neutrophil cytosolic factor 1; D011493:Protein Kinase C