title: Exposure to diesel exhaust upregulates COX-2 expression in ApoE knockout mice.
abstract: BACKGROUND
  We have shown that diesel exhaust (DE) inhalation caused progression of atherosclerosis; however, the mechanisms are not fully understood. We hypothesize that exposure to DE upregulates cyclooxygenase (COX) expression and activity, which could play a role in DE-induced atherosclerosis.
  
  
  METHODS
  ApoE knockout mice (30-week old) fed with regular chow were exposed to DE (at 200 µg/m(3) of particulate matter) or filtered air (control) for 7 weeks (6 h/day, 5 days/week). The protein and mRNA expression of COX-1 and COX-2 were evaluated by immunohistochemistry analysis and quantitative real-time PCR, respectively. To examine COX activity, thoracic aortae were mounted in a wire myograph, and phenylephrine (PE)-stimulated vasoconstriction was measured with and without the presence of COX antagonists (indomethacin). COX-2 activity was further assessed by urine 2,3-dinor-6-keto PGF(1α) level, a major metabolite of prostacyclin I(2) (PGI(2)).
  
  
  RESULTS
  Immunohistochemistry analysis demonstrates that DE exposure enhanced COX-2 expression in both thoracic aorta (p < 0.01) and aortic root (p < 0.03), with no modification of COX-1 expression. The increased COX-2 expression was positively correlated with smooth muscle cell content in aortic lesions (R(2) = 0.4081, p < 0.008). The fractional changes of maximal vasoconstriction in the presence of indomethacin was attenuated by 3-fold after DE exposure (p < 0.02). Urine 2,3-dinor-6-keto PGF(1α) level was 15-fold higher in DE group than the control (p < 0.007). The mRNA expression of COX-2 (p < 0.006) and PGI synthase (p < 0.02), but not COX-1, was significantly augmented after DE exposure.
  
  
  CONCLUSIONS
  We show that DE inhalation enhanced COX-2 expression, which is also associated with phenotypic changes of aortic lesion.
authors: Department of Anesthesiology, Pharmacology & Therapeutics, University of British Columbia, Vancouver, BC, Canada.
authors: Ni
authors: N
authors: Bai
authors: Erin M
authors: EM
authors: Tranfield
authors: Terrance J
authors: TJ
authors: Kavanagh
authors: Joel D
authors: JD
authors: Kaufman
authors: Michael E
authors: ME
authors: Rosenfeld
authors: Stephan F
authors: SF
authors: van Eeden
mesh_terms: D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects / Q000201:enzymology / Q000503:physiopathology; D001057:Apolipoproteins E / Q000235:genetics*; D050197:Atherosclerosis / Q000139:chemically induced / Q000201:enzymology / Q000235:genetics; D051545:Cyclooxygenase 1 / Q000096:biosynthesis; D051546:Cyclooxygenase 2 / Q000096:biosynthesis*; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D004730:Endothelium, Vascular / Q000187:drug effects / Q000201:enzymology / Q000503:physiopathology; D007150:Immunohistochemistry; D007213:Indomethacin / Q000494:pharmacology; D019570:Inhalation Exposure / Q000009:adverse effects*; D008264:Macrophages / Q000187:drug effects / Q000201:enzymology; D008565:Membrane Proteins / Q000096:biosynthesis; D051379:Mice; D018345:Mice, Knockout; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000201:enzymology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015854:Up-Regulation; D014661:Vasoconstriction / Q000187:drug effects / Q000235:genetics; D001335:Vehicle Emissions / Q000633:toxicity*
chemical_list: D001057:Apolipoproteins E; D016861:Cyclooxygenase Inhibitors; D008565:Membrane Proteins; D001335:Vehicle Emissions; C077623:Ptgs2 protein, mouse; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; C496512:Ptgs1 protein, mouse; D007213:Indomethacin