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.
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. METHODS AND 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.[1]References
- 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. Marumo, T., Schini-Kerth, V.B., Fisslthaler, B., Busse, R. Circulation (1997) [Pubmed]
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