l -Arginine Prevents Xanthoma Development and Inhibits Atherosclerosis in LDL Receptor Knockout Mice

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Abstract
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 ω -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.