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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2003;23:97.)
© 2003 American Heart Association, Inc.

Atherosclerosis and Lipoproteins

Effects of Chronic Treatment With L-Arginine on Atherosclerosis in ApoE Knockout and ApoE/Inducible NO Synthase Double-Knockout Mice

Jiqiu Chen; Peter Kuhlencordt; Fumi Urano; Hiroshi Ichinose; Joshua Astern; Paul L. Huang

From the Cardiovascular Research Center and Cardiology Division (J.C., P.K., J.A., P.L.H.), Massachusetts General Hospital and Harvard Medical School, Boston, and the Division of Molecular Genetics (F.U., H.I.), Institute for Comprehensive Medical Science, Fujita Health University, Toyoake, Aichi, Japan.

Correspondence to Paul L. Huang, MD, PhD, Cardiovascular Research Center, Massachusetts General Hospital East, 149 East 13th St, Charlestown, MA 02129. E-mail HuangP{at}helix.mgh.harvard.edu

Objective— L-Arginine serves as a substrate for the formation of NO by the NO synthase (NOS) enzymes. In some studies, dietary supplementation of L-arginine reduces atherosclerosis through the restoration of NO release and improvement in endothelial function. In the present study, we investigate the effect of L-arginine supplementation on the development of atherosclerosis in a mouse model.

Methods and Results— Apolipoprotein E (apoE) knockout (ko) and apoE/inducible NOS (iNOS) double-ko mice were fed a western-type diet with or without L-arginine supplementation in the drinking water (25 g/L). L-Arginine did not affect the lesion area after 16 weeks or 24 weeks in apoE ko mice. However, L-arginine negates the protective effect of iNOS gene deficiency. In contrast to apoE/iNOS dko mice without arginine supplementation, lesion areas were increased in apoE/iNOS double-ko mice with arginine supplementation at 24 weeks. This was associated with an increase in thiobarbituric acid-reactive malondialdehyde adducts, nitrotyrosine staining within lesions, and a decrease in the ratio of reduced tetrahydrobiopterin to total biopterins.

Conclusions— Although L-arginine supplementation does not affect lesion formation in the western-type diet-fed apoE ko mice, it negates the protective effect of iNOS gene deficiency in this model. This raises the possibility that L-arginine supplementation may paradoxically contribute to, rather than reduce, lesion formation by mechanisms that involve lipid oxidation, peroxynitrite formation, and NOS uncoupling.

Key Words: atherosclerosis • arginine • apolipoprotein E • nitric oxide

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