Published online before print December 19, 2002, doi: 10.1161/01.RES.0000052990.68216.EF
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© 2003 American Heart Association, Inc.
Molecular Medicine |
Regulation of Cytokine-Induced Nitric Oxide Synthesis by Asymmetric Dimethylarginine
Role of Dimethylarginine Dimethylaminohydrolase
From the Department of Internal Medicine III and the Cardiovascular Research Institute (S.U., H.M., T.I.), Department of Pathology (S.K., M.M.), and Department of Nephrology (S.O.), Kurume University School of Medicine, Kurume and Department of Nutritional Science (M.K.), Faculty of Health and Welfare Science, Okayama Prefectural University, Soja, Japan.
Correspondence to Seiya Kato, MD, PhD, Department of Pathology, Kurume University, School of Medicine, 67 Asahi-machi, Kurume 830-0011, Japan. E-mail seikato{at}med.kurume-u.ac.jp
In response to vascular insults, inflammatory cytokines stimulate vascular smooth muscle cells (SMCs) to express an inducible isoform of nitric oxide synthase (iNOS). Asymmetric dimethylarginine (ADMA), an endogenous NO synthase inhibitor, is metabolized by dimethylarginine dimethylaminohydrolase (DDAH). To determine whether the ADMA-DDAH system regulates cytokine-induced NO production, cultured rat SMCs were exposed to interleukin-1ß (IL-1ß). IL-1ß (1 to 100 U/mL) dose-dependently stimulated not only iNOS but also DDAH expression and enzyme activity, accompanied by an increase in NO metabolite and by a decrease in ADMA content in culture media. A DDAH inhibitor (4124W, 5 mmol/L) augmented ADMA production (P<0.01) and decreased NO synthesis (P<0.01) in IL-1ß–stimulated SMCs. On the other hand, an adenovirus-mediated overexpression of DDAH reduced ADMA and enhanced NO production. Exogenous administration of NO donors (SNAP and SIN-1) dose-dependently increased NO metabolite in the culture media but had no effect on ADMA. Our results indicate two mechanisms of IL-1ß–induced NO synthesis: the direct stimulation of the expression of iNOS and the indirect stimulation of iNOS activity by upregulating DDAH and reducing ADMA. The ADMA-DDAH system may be another regulatory mechanism of inflammation-mediated NO production for human vascular diseases.
Key Words: nitric oxide • nitric oxide synthase • interleukins • smooth muscle • atherosclerosis
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