title: Exposure to diesel exhaust up-regulates iNOS expression in ApoE knockout mice.
abstract: Traffic related particulate matter air pollution is a risk factor for cardiovascular events; however, the biological mechanisms are unclear. We hypothesize that diesel exhaust (DE) inhalation induces up-regulation of inducible nitric oxide synthase (iNOS), which is known to contribute to vascular dysfunction, progression of atherosclerosis and ultimately cardiovascular morbidity and mortality.
  
  
  METHODS
  ApoE knockout mice (30-week) were exposed to DE (at 200 μg/m³ of particulate matter) or filtered-air (control) for 7 weeks (6 h/day, 5 days/week). iNOS expression in the blood vessels and heart was evaluated by immunohistochemistry and western blotting analysis. To examine iNOS activity, thoracic aortae were mounted in a wire myograph, and vasoconstriction stimulated by phenylephrine (PE) was measured with and without the presence of the specific inhibitor for iNOS (1400 W). NF-κB (p65) activity was examined by ELISA. The mRNA expression of iNOS and NF-κB (p65) was determined by real-time PCR.
  
  
  RESULTS
  DE exposure significantly enhanced iNOS expression in the thoracic aorta (4-fold) and heart (1.5 fold). DE exposure significantly attenuated PE-stimulated vasoconstriction by ~20%, which was partly reversed by 1400 W. The mRNA expression of iNOS and NF-κB was significantly augmented after DE exposure. NF-κB activity was enhanced 2-fold after DE inhalation, and the augmented NF-κB activity was positively correlated with iNOS expression (R²=0.5998).
  
  
  CONCLUSIONS
  We show that exposure to DE increases iNOS expression and activity possibly via NF-κB-mediated pathway. We suspect that DE exposure-caused up-regulation of iNOS contributes to vascular dysfunction and atherogenesis, which could ultimately lead to urban air pollution-associated cardiovascular morbidity and mortality.
authors: Department of Anesthesiology, Pharmacology & Therapeutics, University of British Columbia, Vancouver, BC, Canada.
authors: Ni
authors: N
authors: Bai
authors: Takashi
authors: T
authors: Kido
authors: Terrance J
authors: TJ
authors: Kavanagh
authors: Joel D
authors: JD
authors: Kaufman
authors: Michael E
authors: ME
authors: Rosenfeld
authors: Cornelis
authors: C
authors: van Breemen
authors: Stephan F
authors: SF
authors: van Eeden
mesh_terms: D000578:Amidines / Q000494:pharmacology; D000818:Animals; D001013:Aorta, Thoracic / Q000201:enzymology / Q000378:metabolism; D001057:Apolipoproteins E / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D050197:Atherosclerosis / Q000139:chemically induced* / Q000201:enzymology / Q000378:metabolism; D001596:Benzylamines / Q000494:pharmacology; D018955:CD36 Antigens / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009206:Myocardium / Q000201:enzymology; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000235:genetics; D052638:Particulate Matter / Q000633:toxicity*; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D014443:Tyrosine / Q000031:analogs & derivatives / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects; D014661:Vasoconstriction / Q000502:physiology; D001335:Vehicle Emissions / Q000633:toxicity*
chemical_list: D000578:Amidines; D001057:Apolipoproteins E; D001596:Benzylamines; D018955:CD36 Antigens; D004791:Enzyme Inhibitors; C104820:N-(3-(aminomethyl)benzyl)acetamidine; D016328:NF-kappa B; D052638:Particulate Matter; D012333:RNA, Messenger; D001335:Vehicle Emissions; C002744:3-nitrotyrosine; D014443:Tyrosine; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse