NITRIC-OXIDE INHIBITS MACROPHAGE-COLONY-STIMULATING FACTOR GENE-TRANSCRIPTION IN VASCULAR ENDOTHELIAL-CELLS

Macrophage-colony stimulating factor (M-CSF) contributes to atherogene sis by regulating macrophage-derived foam cells in atherosclerotic les ions. Here we report that nitric oxide (NO) inhibits the expression of M-CSF in human vascular endothelial cells independent of guanylyl cyc lase activation. The induction of M-CSF mRNA expression by either oxid ized low density lipoprotein (ox-LDL) or tumor necrosis factor-alpha ( TNF alpha) was attenuated by NO donors, S-nitrosoglutathione (GSNO), s odium nitroprusside (SNP), and 3-morpholinosydnonimine, but not by cGM P analogues, glutathione, or nitrite. Inhibition of endogenous NO prod uction by N-monomethyl-L-arginine (L-NMA) also increased M-CSF express ion in control and TNF alpha-stimulated cells. Nuclear run-on assays a nd transfection studies using M-CSF promoter constructs linked to chlo ramphenicol acetyltransferase reporter gene indicated that NO represse d M-CSF gene transcription through nuclear factor-kappa B (NF-kappa B) . Electrophoretic mobility shift assays demonstrated that activation o f NF-kappa B by L-NMA, ox-LDL, and TNF alpha was attenuated by GSNO an d SNP, but not by glutathione or cGMP analogues. Since the induction o f M-CSF expression depends upon NF-kappa B activation, the ability of NO to inhibit NF-kappa B activation and M-CSF expression may contribut e to some of NO's antiatherogenic properties.