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.