Roles of NF-κB and SP-1 in Oxidative Stress-Mediated Induction of Platelet-Derived Growth Factor-B by TNFα in Human Endothelial Cells

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Platelet-derived growth factor-B (PDGF-B) is upregulated by proinflamatory stimuli in the early stages of atherosclerosis. However, its mechanisms are not fully elucidated. In the present study, by using the antioxidant N-acetylcysteine (NAC), we investigated in human umbilical vein endothelial cells (HUVECs) the roles of oxidative stress in PDGF-B expression induced by tumor necrosis factor α (TNFα) and its underlying mechanisms. Exposure of HUVECs to TNFα (200 U/ml) for 24 hours caused significant increases of both the PDGF-B expression and its promoter/enhancer activity, which were abolished by NAC (20 mmol/L). Accordingly, a prolonged oxidative stress was induced by TNFα and that was prevented by pretreatment with NAC. Electrophoresis mobility shift assay (EMSA) and Western blot analysis showed that both the nuclear factor-κB (NF-κB) and the specificity protein-1 (SP-1) were activated by TNFα. However, NAC only partially inhibited the TNFα-induced activation of NF-κB, but abolished the activation of SP-1. Mutation of the NF-κB binding site resulted in a moderate reduction in the TNFα-induced activity of PDGF-B promoter/enhancer, whereas mutation of SP-1 binding site resulted in an absence of induction by TNFα. These results suggest that oxidative stress mediates the TNFα-induced expression of PDGF-B in HUVECs through redox-sensitive transcription factors, predominantly the SP-1 and possibly, to some extent of NF-κB.

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