Effects of chronic treatment with L-arginine on atherosclerosis in apoE knockout and apoE/inducible NO synthase double-knockout mice.
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.


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.
Chen
Jiqiu
J
Cardiovascular Research Center and Cardiology Division, Massachusetts General Hospital and Harvard Medical School, Boston, USA.
Kuhlencordt
Peter
P
Urano
Fumi
F
Ichinose
Hiroshi
H
Astern
Joshua
J
Huang
Paul L
PL
D000818:Animals; D001011:Aorta / Q000737:chemistry / Q000201:enzymology / Q000502:physiology; D001057:Apolipoproteins E / Q000172:deficiency* / Q000235:genetics* / Q000502:physiology; D001120:Arginine / Q000008:administration & dosage* / Q000378:metabolism; D001161:Arteriosclerosis / Q000201:enzymology / Q000235:genetics* / Q000378:metabolism* / Q000503:physiopathology; D001708:Biopterins / Q000097:blood; D015153:Blotting, Western; D002784:Cholesterol / Q000097:blood; D004195:Disease Models, Animal; D007150:Immunohistochemistry; D007527:Isoenzymes / Q000276:immunology; D008315:Malondialdehyde / Q000097:blood; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009569:Nitric Oxide / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000172:deficiency* / Q000235:genetics* / Q000276:immunology / Q000502:physiology; D052247:Nitric Oxide Synthase Type II; D013194:Staining and Labeling; D017392:Thiobarbituric Acid Reactive Substances / Q000378:metabolism; D014443:Tyrosine / Q000031:analogs & derivatives* / Q000276:immunology
D001057:Apolipoproteins E; D007527:Isoenzymes; D017392:Thiobarbituric Acid Reactive Substances; D001708:Biopterins; D009569:Nitric Oxide; C002744:3-nitrotyrosine; D014443:Tyrosine; D008315:Malondialdehyde; D001120:Arginine; D002784:Cholesterol; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse