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L-arginine prevents xanthoma development and inhibits atherosclerosis in LDL receptor knockout mice
1Department of Medicine, Columbia University College of Physicians and Surgeons, New York, NY 10032, USA.
Background:
The potential antiatherosclerotic actions of NO were investigated in four groups of mice (n = 10 per group) lacking functional LDL receptor genes, an animal model of familial hypercholesterolemia. Group 1 was fed a regular chow diet. Groups 2 through 4 were fed a 1.25% high-cholesterol diet. In addition, group 3 received supplemental L-arginine and group 4 received L-arginine and N omega-nitro-L-arginine (L-NA), an inhibitor of NO synthase (NOS).
Methods And Results:
Animals were killed at 6 months; aortas were stained with oil red O for planimetry and with antibodies against constitutive and inducible NOSs. Plasma cholesterol was markedly increased in the animals receiving the high-cholesterol diet. Xanthomas appeared in all mice fed the high-cholesterol diet alone but not in those receiving L-arginine. Aortic atherosclerosis was present in all mice on the high-cholesterol diet. The mean atherosclerotic lesion area was reduced significantly (P < .01) in the cholesterol-fed mice given L-arginine compared with those receiving the high-cholesterol diet alone. The mean atherosclerotic lesion area was significantly larger (P < .01) in cholesterol-fed mice receiving L-arginine + L-NA than in those on the high-cholesterol diet alone. Within the atherosclerotic plaques, endothelial cells immunoreacted for endothelial cell NOS; macrophages, foam cells, and smooth muscle cells immunostained strongly for inducible NOS and nitrotyrosine residues.
Conclusions:
The data indicate that L-arginine prevents xanthoma formation and reduces atherosclerosis in LDL receptor knockout mice fed a high-cholesterol diet. The abrogation of the beneficial effects of L-arginine by L-NA suggests that the antiatherosclerotic actions of L-arginine are mediated by NOS. The data suggest that L-arginine may be beneficial in familial hypercholesterolemia.
Insights
L-arginine supplementation reduced atherosclerosis and prevented xanthoma formation in a mouse model of familial hypercholesterolemia. These beneficial effects were mediated by nitric oxide synthase (NOS), suggesting L-arginine may help treat this condition.
Area of Science:
- Cardiovascular Research
- Metabolic Disorders
- Nitric Oxide Biology
Background:
- Familial hypercholesterolemia (FH) is characterized by high LDL cholesterol and accelerated atherosclerosis.
- Nitric oxide (NO) is known to have antiatherosclerotic properties.
- LDL receptor knockout mice serve as a model for FH.
Purpose of the Study:
- To investigate the antiatherosclerotic effects of L-arginine in LDL receptor knockout mice.
- To determine if these effects are mediated by nitric oxide synthase (NOS).
Main Methods:
- Four groups of LDL receptor knockout mice were used.
- Mice were fed either a regular chow or a high-cholesterol diet.
- Supplementation with L-arginine and/or N omega-nitro-L-arginine (L-NA), a NOS inhibitor, was administered.
- Aortic atherosclerosis and xanthoma formation were assessed.
Main Results:
- High-cholesterol diet increased plasma cholesterol and induced atherosclerosis and xanthomas.
- L-arginine supplementation significantly reduced atherosclerotic lesion area and prevented xanthomas.
- L-NA abrogated the protective effects of L-arginine, indicating NOS mediation.
- NOS and nitrotyrosine were detected within atherosclerotic plaques.
Conclusions:
- L-arginine demonstrates antiatherosclerotic properties in a mouse model of FH.
- The antiatherosclerotic effects of L-arginine are mediated by NOS.
- L-arginine may hold therapeutic potential for patients with familial hypercholesterolemia.