title: Benzo[a]pyrene induces the transcription of cyclooxygenase-2 in vascular smooth muscle cells. Evidence for the involvement of extracellular signal-regulated kinase and NF-kappaB.
abstract: Polycyclic aromatic hydrocarbons, such as benzo[a]pyrene (B[a]P) present in tobacco smoke and tar, have been implicated in the development of atherosclerosis as well as cancer. Increased expression of cyclooxygenase-2 (COX-2) has been detected both in atherosclerotic lesions and in epithelial cancers. To determine whether polycyclic aromatic hydrocarbons might directly affect COX expression in vascular cells, we investigated the effects of B[a]P on COX-2 expression in human and rat arterial smooth muscle cells (SMC). Treatment with B[a]P increased levels of COX-2 protein and mRNA and enhanced prostaglandin synthesis. Nuclear runoff assays and transient transfections revealed increased COX-2 gene transcription after treatment with B[a]P. Experiments were done to define the signaling mechanism by which B[a]P induced COX-2. B[a]P caused a rapid increase in phosphorylation of extracellular signal-regulated kinase (ERK); pharmacologic inhibition of mitogen-activated protein kinase kinase blocked B[a]P-mediated induction of COX-2. Depletion of the intracellular antioxidant, glutathione, with buthionine sulfoximine significantly increased B[a]P-mediated induction of COX-2 while exposure to N-acetylcysteine, a precursor of glutathione, suppressed the induction of COX-2 by B[a]P. Several lines of evidence suggest that the induction of COX-2 by B[a]P is mediated, at least in part, by NF-kappaB. Treatment with B[a]P increased binding of NF-kappaB to DNA. Moreover, B[a]P-mediated stimulation of COX-2 promoter activity was blocked when a construct containing a mutagenized NF-kappaB site was used. Pharmacological inhibitors of NF-kappaB blocked the induction of COX-2 protein and the stimulation of COX-2 promoter activity by B[a]P. Taken together, these data are likely to be important for understanding the atherogenic effects of tobacco smoke.
authors.affiliation: Departments of Medicine, New York Presbyterian Hospital-Weill Medical College of Cornell University, New York, New York 10021, USA.
authors.forename: Z
authors.initials: Z
authors.lastname: Yan
authors.forename: K
authors.initials: K
authors.lastname: Subbaramaiah
authors.forename: T
authors.initials: T
authors.lastname: Camilli
authors.forename: F
authors.initials: F
authors.lastname: Zhang
authors.forename: T
authors.initials: T
authors.lastname: Tanabe
authors.forename: T A
authors.initials: TA
authors.lastname: McCaffrey
authors.forename: A J
authors.initials: AJ
authors.lastname: Dannenberg
authors.forename: B B
authors.initials: BB
authors.lastname: Weksler
mesh_terms: D000818:Animals; D001483:Base Sequence; D001564:Benzo(a)pyrene / Q000494:pharmacology*; D051546:Cyclooxygenase 2; D017931:DNA Primers; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects*; D006801:Humans; D007527:Isoenzymes / Q000235:genetics*; D008565:Membrane Proteins; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology; D016328:NF-kappa B / Q000378:metabolism*; D018384:Oxidative Stress; D011451:Prostaglandin-Endoperoxide Synthases / Q000235:genetics*; D051381:Rats; D014158:Transcription, Genetic / Q000187:drug effects*
chemical_list: D017931:DNA Primers; D007527:Isoenzymes; D008565:Membrane Proteins; D016328:NF-kappa B; D001564:Benzo(a)pyrene; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; D020928:Mitogen-Activated Protein Kinases