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

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Abstract
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.