Nitric Oxide Inhibits Macrophage-Colony Stimulating Factor Gene Transcription in Vascular Endothelial Cells (*)
- From the (1)Cardiovascular Division, Brigham & Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115
- § To whom correspondence and reprint requests should be addressed: Cardiovascular Division, Department of Medicine, 221 Longwood Ave., LMRC-307, Boston, MA 02115. Tel.: 617-732-6538; Fax: 617-732-6961.
Abstract
Macrophage-colony stimulating factor (M-CSF) contributes to atherogenesis by regulating macrophage-derived foam cells in atherosclerotic lesions. Here we report that nitric oxide (NO) inhibits the expression of M-CSF in human vascular endothelial cells independent of guanylyl cyclase activation. The induction of M-CSF mRNA expression by either oxidized low density lipoprotein (ox-LDL) or tumor necrosis factor-α (TNFα) was attenuated by NO donors, S-nitrosoglutathione (GSNO), sodium nitroprusside (SNP), and 3-morpholinosydnonimine, but not by cGMP analogues, glutathione, or nitrite. Inhibition of endogenous NO production by N-monomethyl-L-arginine (L-NMA) also increased M-CSF expression in control and TNFα-stimulated cells. Nuclear run-on assays and transfection studies using M-CSF promoter constructs linked to chloramphenicol acetyltransferase reporter gene indicated that NO repressed M-CSF gene transcription through nuclear factor-κB (NF-κB). Electrophoretic mobility shift assays demonstrated that activation of NF-κB by L-NMA, ox-LDL, and TNFα was attenuated by GSNO and SNP, but not by glutathione or cGMP analogues. Since the induction of M-CSF expression depends upon NF-κB activation, the ability of NO to inhibit NF-κB activation and M-CSF expression may contribute to some of NO's antiatherogenic properties.
Footnotes
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↵* This work was supported by National Institutes of Health Grants HL02508 (to J. K. L.) and HL34636 (to P. L.) and an American Heart Association grant-in-aid award (to J. K. L.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore by hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
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↵1 The abbreviations used are:
- M-CSF
-
macrophage colony stimulating factor
- NO
-
nitric oxide
- GSNO
-
S-nitrosoglutathione
- TNFα
-
tumor necrosis factor α
- ox-LDL
-
oxidized low density lipoprotein
- RSV
-
Rous sarcoma virus
- TBARS
-
thiobarbituric acid reactive substances
- CAT
-
chloramphenicol acetyltransferase
- SNP
-
sodium nitroprusside
- L-NMA
-
N-monomethyl-L-arginine.
