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(Circulation. 1997;96:934-940.)
© 1997 American Heart Association, Inc.

Articles

Nitric Oxide Regulates Monocyte Chemotactic Protein-1

Philip S. Tsao, PhD; Bing-yin Wang, MD, PhD; Ricardo Buitrago, MD; John Y.-J. Shyy, MD; ; John P. Cooke, MD, PhD

From the Section of Vascular Medicine, Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, Calif, and the Department of Bioengineering and Institute for Biomedical Engineering, University of California at San Diego, La Jolla (J.Y.-J.S.).

Correspondence to John P. Cooke, MD, PhD, Division of Cardiovascular Medicine, Stanford University, 300 Pasteur Dr, Stanford, CA 94305-5246. E-mail john.cooke{at}forsythe.stanford.edu

Background Monocyte chemotactic protein-1 (MCP-1) is a 76-amino-acid chemokine thought to be the major chemotactic factor for monocytes. We and others have demonstrated that NO inhibits monocyte–endothelial cell interactions and atherogenesis. We hypothesize that the antiatherogenic effect of NO may be due in part to its inhibition of MCP-1 expression.

Methods and Results Smooth muscle cells (SMCs) were isolated from normal rabbit aortas by the explant method. Cells were then exposed to LPS (10 µg/mL), native LDL, or oxidized LDL (30 µg/mL) for 6 hours. The expression of MCP-1 in SMCs and chemotactic activity in the conditioned medium were induced by lipopolysaccharide (LPS) or by oxidized LDL but not native LDL. The induction of MCP-1 by cytokines or oxidized lipoproteins was associated with an increased generation of superoxide anion by the SMCs and increased activity of the transcriptional protein nuclear factor-B (NFB). The induced expression of MCP-1 and activation of NFB were reduced by previous exposure of the SMCs to the NO donor DETA-NONOate (100 µmol/L) (P<.05). To determine whether NO exerted its effect at a transcriptional level, SMCs and COS cells were transfected with a 400-bp fragment of the MCP-1 promoter. Promoter activity was enhanced by oxidized LDL, and LPS was inhibited by DETA-NO. Nuclear run-on assays confirmed that the effect of NO occurred at a transcriptional level. To investigate the role of endogenous NO in the regulation of MCP-1 in vivo, New Zealand White rabbits were fed normal chow, normal chow plus nitro-L-arginine (LNA), high-cholesterol diet (Chol), or high-cholesterol diet supplemented with L-arginine (Arg). After 2 weeks, thoracic aortas were harvested and total RNA was isolated. Northern analysis using full-length MCP-1 cDNA demonstrated increased expression in Chol and LNA aortas; this expression was decreased in aortas from Arg animals.

Conclusions These studies indicate that the antiatherogenic effect of NO may be mediated in part by its inhibition of MCP-1 expression.

Key Words: nitric oxide • muscle, smooth • cholesterol

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