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Title: Exposure to diesel exhaust up-regulates iNOS expression in ApoE knockout mice

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 {mu}g/m{sup 3} 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-{kappa}B (p65) activity was examined by ELISA. The mRNA expression of iNOS and NF-{kappa}B (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 {approx} 20%, which was partly reversed by 1400 W. The mRNA expression of iNOS and NF-{kappa}B was significantly augmented after DE exposure. NF-{kappa}B activity was enhanced 2-fold after DE inhalation, andmore » the augmented NF-{kappa}B activity was positively correlated with iNOS expression (R{sup 2} = 0.5998). Conclusions: We show that exposure to DE increases iNOS expression and activity possibly via NF-{kappa}B-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. - Highlights: > Exposed ApoE knockout mice (30-week) to diesel exhaust (DE) for 7 weeks. > Examine iNOS expression and activity in the blood vessels and heart. > DE exposure enhanced iNOS protein and mRNA expression in the aorta and heart. > iNOS activity was also increased after DE exposure. > This up-regulation of iNOS may contribute to vascular dysfunction and atherogenesis.« less
Authors:
 [1] ;  [2] ;  [3] ; ; ;  [4] ;  [1] ;  [3]
  1. Department of Anesthesiology, Pharmacology and Therapeutics, University of British Columbia, Vancouver, BC (Canada)
  2. (Canada)
  3. James Hogg Research Centre, Providence Heart and Lung Institute, St. Paul's Hospital, University of British Columbia, Vancouver, BC (Canada)
  4. Department of Occupational and Environmental Health, University of Washington, Seattle, WA (United States)
Publication Date:
OSTI Identifier:
21587826
Resource Type:
Journal Article
Resource Relation:
Journal Name: Toxicology and Applied Pharmacology; Journal Volume: 255; Journal Issue: 2; Other Information: DOI: 10.1016/j.taap.2011.06.013; PII: S0041-008X(11)00235-3; Copyright (c) 2011 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; Country of input: International Atomic Energy Agency (IAEA)
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; AIR POLLUTION; AORTA; ARTERIOSCLEROSIS; ENZYME IMMUNOASSAY; HAZARDS; HEART; HYPOXANTHINE PHOSPHORIBOSYLTRANSFERASE; INHALATION; KNOCK-OUT REACTIONS; LEUKOCYTES; LIPOPROTEINS; MACROPHAGES; MESSENGER-RNA; MICE; MORTALITY; NITRIC OXIDE; POLYMERASE CHAIN REACTION; VASOCONSTRICTION ANIMAL CELLS; ANIMALS; ARTERIES; BIOASSAY; BIOLOGICAL MATERIALS; BLOOD; BLOOD CELLS; BLOOD VESSELS; BODY; BODY FLUIDS; CARDIOVASCULAR DISEASES; CARDIOVASCULAR SYSTEM; CHALCOGENIDES; CONNECTIVE TISSUE CELLS; DIRECT REACTIONS; DISEASES; ENZYMES; GENE AMPLIFICATION; GLYCOSYL TRANSFERASES; IMMUNOASSAY; INTAKE; LIPIDS; MAMMALS; MATERIALS; NITROGEN COMPOUNDS; NITROGEN OXIDES; NUCLEAR REACTIONS; NUCLEIC ACIDS; ORGANIC COMPOUNDS; ORGANS; OXIDES; OXYGEN COMPOUNDS; PENTOSYL TRANSFERASES; PHAGOCYTES; POLLUTION; PROTEINS; RNA; RODENTS; SOMATIC CELLS; TRANSFERASES; VASCULAR DISEASES; VERTEBRATES