title: Platelet-derived growth factor-stimulated superoxide anion production modulates activation of transcription factor NF-kappaB and expression of monocyte chemoattractant protein 1 in human aortic smooth muscle cells.
abstract: BACKGROUND
  Platelet-derived growth factor (PDGF) and superoxide anion (O2.-) have been implicated in vascular diseases. We investigated whether PDGF stimulates the production of O2.- in human aortic smooth muscle cells (HSMCs) and whether O2.- leads in this way to the activation of nuclear factor-kappaB (NF-kappaB) and induction of monocyte chemoattractant protein 1 (MCP-1) in PDGF-stimulated HSMCs.
  
  
  RESULTS
  PDGF-AB concentration- and time-dependently stimulated O2.- generation from HSMCs. The stimulatory effect of PDGF-AB was mimicked by PDGF-BB but not by PDGF-AA. The generation of O2.- by PDGF-AB was attenuated by the NAD(P)H oxidase inhibitor iodonium diphenyl, the specific protein kinase C (PKC) inhibitor Ro 31-8220, and the phosphatidylinositol 3-kinase inhibitor wortmannin. Allopurinol and nifedipine had no effect on PDGF-AB-induced O2.- release, whereas indomethacin potentiated this response. Gel mobility shift assay revealed that PDGF-AB increased the binding activity of NF-kappaB, which contained predominantly the p50/p65 heterodimer in nuclear extracts from HSMCs. Superoxide dismutase as well as iodonium diphenyl, Ro 31-8220, and wortmannin attenuated PDGF-AB-induced activation of NF-kappaB and expression of MCP-1 mRNA. In contrast, superoxide dismutase did not inhibit the interleukin-1beta-induced NF-kappaB activation.
  
  
  CONCLUSIONS
  The results demonstrate that PDGF stimulates O2.- generation in HSMCs via PKC-dependent and wortmannin-sensitive pathways involving flavoenzyme(s). This PDGF-induced O2.- production may be involved in vascular lesion formation by mediating, at least in part, NF-kappaB activation and MCP-1 induction.
authors.affiliation: Zentrum der Physiologie, Klinikum der Johann Wolfgang Goethe Universität, Frankfurt am Main, Germany.
authors.forename: T
authors.initials: T
authors.lastname: Marumo
authors.forename: V B
authors.initials: VB
authors.lastname: Schini-Kerth
authors.forename: B
authors.initials: B
authors.lastname: Fisslthaler
authors.forename: R
authors.initials: R
authors.lastname: Busse
mesh_terms: D000493:Allopurinol / Q000494:pharmacology; D000730:Androstadienes / Q000494:pharmacology; D001013:Aorta, Thoracic / Q000187:drug effects* / Q000378:metabolism; D000077214:Becaplermin; D001713:Biphenyl Compounds / Q000494:pharmacology; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000096:biosynthesis*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D007375:Interleukin-1 / Q000494:pharmacology; D009097:Multienzyme Complexes / Q000037:antagonists & inhibitors; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000378:metabolism; D009247:NADH, NADPH Oxidoreductases / Q000037:antagonists & inhibitors; D019255:NADPH Oxidases / Q000037:antagonists & inhibitors; D016328:NF-kappa B / Q000378:metabolism*; D009543:Nifedipine / Q000494:pharmacology; D009861:Onium Compounds / Q000494:pharmacology; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010982:Platelet-Derived Growth Factor / Q000494:pharmacology*; D011493:Protein Kinase C / Q000037:antagonists & inhibitors; D020574:Proto-Oncogene Proteins c-sis; D012333:RNA, Messenger / Q000096:biosynthesis; D013482:Superoxide Dismutase / Q000494:pharmacology; D013481:Superoxides / Q000378:metabolism*; D014158:Transcription, Genetic / Q000187:drug effects*; D000077191:Wortmannin
chemical_list: D000730:Androstadienes; D001713:Biphenyl Compounds; D018932:Chemokine CCL2; D004791:Enzyme Inhibitors; D007211:Indoles; D007375:Interleukin-1; D009097:Multienzyme Complexes; D016328:NF-kappa B; D009861:Onium Compounds; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010982:Platelet-Derived Growth Factor; D020574:Proto-Oncogene Proteins c-sis; D012333:RNA, Messenger; C075278:platelet-derived growth factor A; C031291:diphenyliodonium; D013481:Superoxides; D000077214:Becaplermin; D000493:Allopurinol; D013482:Superoxide Dismutase; C023107:NADH oxidase; D009247:NADH, NADPH Oxidoreductases; D019255:NADPH Oxidases; D011493:Protein Kinase C; D009543:Nifedipine; C064758:Ro 31-8220; D000077191:Wortmannin