Platelet-derived growth factor–stimulated superoxide anion production modulates activation of transcription factor NF-κB and expression of monocyte chemoattractant …

T Marumo, VB Schini-Kerth, B Fisslthaler, R Busse - Circulation, 1997 - Am Heart Assoc
T Marumo, VB Schini-Kerth, B Fisslthaler, R Busse
Circulation, 1997Am Heart Assoc
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–κB (NF-κB) 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 …
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–κB (NF-κB) 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-κB, 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-κB and expression of MCP-1 mRNA. In contrast, superoxide dismutase did not inhibit the interleukin-1β–induced NF-κB 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-κB activation and MCP-1 induction.
Am Heart Assoc