title: Mechanisms of oxidative stress in human aortic aneurysms--association with clinical risk factors for atherosclerosis and disease severity.
abstract: Aortic abdominal aneurysms (AAA) are important causes of cardiovascular morbidity and mortality. Oxidative stress may link multiple mechanisms of AAA including vascular inflammation and increased metalloproteinase activity. However, the mechanisms of vascular free radical production remain unknown. Accordingly, we aimed to determine sources and molecular regulation of vascular superoxide (O2(-)) production in human AAA.
  
  
  RESULTS
  AAA segments and matched non-dilated aortic samples were obtained from 40 subjects undergoing AAA repair. MDA levels (determined by HPLC/MS) were greater in plasma of AAA subjects (n=16) than in risk factor matched controls (n=16). Similarly, superoxide production, measured by lucigenin chemiluminescence and dihydroethidium fluorescence, was increased in aneurysmatic segments compared to non-dilated aortic specimens. NADPH oxidases and iNOS are the primary sources of O2(-) in AAA. Xanthine oxidase, mitochondrial oxidases and cyclooxygenase inhibition had minor or no effect. Protein kinase C inhibition had no effect on superoxide production in AAA. NADPH oxidase subunit mRNA levels for p22phox, nox2 and nox5 were significantly increased in AAAs while nox4 mRNA expression was lower. Superoxide production was higher in subjects with increased AAA repair risk Vanzetto score and was significantly associated with smoking, hypercholesterolemia and presence of CAD in AAA cohort. Basal superoxide production and NADPH oxidase activity were correlated to aneurysm size.
  
  
  CONCLUSIONS
  Increased expression and activity of NADPH oxidases are important mechanisms underlying oxidative stress in human aortic abdominal aneurysm. Uncoupled iNOS may link oxidative stress to inflammation in AAA. Oxidative stress is related to aneurysm size and major clinical risk factors in AAA patients.
authors.affiliation: Translational Medicine Laboratory, Department of Internal and Agricultural Medicine, Jagiellonian University School of Medicine, Cracow, Poland; Department of Interventional Cardiology, Institute of Cardiology, Jagiellonian University School of Medicine, Cracow, Poland.
authors.forename: Bartłomiej
authors.initials: B
authors.lastname: Guzik
authors.forename: Agnieszka
authors.initials: A
authors.lastname: Sagan
authors.forename: Dominik
authors.initials: D
authors.lastname: Ludew
authors.forename: Wojciech
authors.initials: W
authors.lastname: Mrowiecki
authors.forename: Maciej
authors.initials: M
authors.lastname: Chwała
authors.forename: Beata
authors.initials: B
authors.lastname: Bujak-Gizycka
authors.forename: Grzegorz
authors.initials: G
authors.lastname: Filip
authors.forename: Grzegorz
authors.initials: G
authors.lastname: Grudzien
authors.forename: Boguslaw
authors.initials: B
authors.lastname: Kapelak
authors.forename: Krzysztof
authors.initials: K
authors.lastname: Zmudka
authors.forename: Tomasz
authors.initials: T
authors.lastname: Mrowiecki
authors.forename: Jerzy
authors.initials: J
authors.lastname: Sadowski
authors.forename: Ryszard
authors.initials: R
authors.lastname: Korbut
authors.forename: Tomasz J
authors.initials: TJ
authors.lastname: Guzik
mesh_terms: D000368:Aged; D017544:Aortic Aneurysm, Abdominal / Q000150:complications* / Q000378:metabolism*; D050197:Atherosclerosis / Q000453:epidemiology / Q000209:etiology* / Q000378:metabolism*; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D019255:NADPH Oxidases / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D018384:Oxidative Stress; D012307:Risk Factors; D012720:Severity of Illness Index; D013481:Superoxides / Q000378:metabolism
chemical_list: D013481:Superoxides; C496319:NOS2 protein, human; D052247:Nitric Oxide Synthase Type II; D019255:NADPH Oxidases
keywords: Aortic abdominal aneurysm; Inflammation; NAD(P)H oxidase; Oxidant stress; Reactive oxygen species; Superoxide