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-κB Academic Article Article uri icon

Overview

MeSH Major

  • Adiponectin
  • Adipose Tissue, White
  • Aromatase
  • Breast
  • C-Reactive Protein
  • Interleukin-6
  • Leptin
  • Menopause

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.

publication date

  • February 18, 2000

Research

keywords

  • Academic Article

Identity

Digital Object Identifier (DOI)

  • 10.1074/jbc.275.7.4949

PubMed ID

  • 10671533

Additional Document Info

start page

  • 4949

end page

  • 55

volume

  • 275

number

  • 7