期刊
JOURNAL OF BIOLOGICAL CHEMISTRY
卷 275, 期 7, 页码 4949-4955出版社
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.275.7.4949
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资金
- NHLBI NIH HHS [HL55627, HL5699987] Funding Source: Medline
- NIA NIH HHS [AG12712] Funding Source: Medline
Polycyclic aromatic hydrocarbons, such as benzo[alpha]pyrene (B[alpha]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[alpha]P on COX-2 expression in human and rat arterial smooth muscle cells (SMC), Treatment with B[alpha]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[alpha]P. Experiments were done to define the signaling mechanism by which B[alpha]P induced COX-2, B[alpha]P caused a rapid increase in phosphorylation of extracellular signal-regulated kinase (ERK); pharmacologic inhibition of mitogen-activated protein kinase kinase blocked B[alpha]P-mediated induction of COX-2, Depletion of the intracellular antioxidant, glutathione, with buthionine sulfoximine significantly increased B[alpha]P-mediated induction of COX-2 while exposure to N-acetylcysteine, a precursor of glutathione, suppressed the induction of COX-2 by B[alpha]P. Several lines of evidence suggest that the induction of COX-2 by B[alpha]P is mediated, at least in part, by NF-kappa B, Treatment with B[alpha]P increased binding of NF-kappa B to DNA. Moreover, B[alpha]P-mediated stimulation of COX-2 promoter activity was blocked when a construct containing a mutagenized NF-kappa B site was used. Pharmacological inhibitors of NF-kappa B blocked the induction of COX-2 protein and the stimulation of COX-2 promoter activity by B[alpha]P, Taken together, these data are likely to be important for understanding the atherogenic effects of tobacco smoke.
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