L-arginine prevents xanthoma development and inhibits atherosclerosis in LDL receptor knockout mice.
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).


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.
Aji
W
W
Department of Medicine, Columbia University College of Physicians and Surgeons, New York, NY 10032, USA.
Ravalli
S
S
Szabolcs
M
M
Jiang
X C
XC
Sciacca
R R
RR
Michler
R E
RE
Cannon
P J
PJ
D000818:Animals; D001011:Aorta / Q000473:pathology; D001120:Arginine / Q000494:pharmacology*; D001161:Arteriosclerosis / Q000473:pathology / Q000517:prevention & control*; D002791:Cholesterol, Dietary / Q000494:pharmacology; D005260:Female; D006937:Hypercholesterolemia / Q000235:genetics; D008297:Male; D051379:Mice; D018345:Mice, Knockout / Q000235:genetics* / Q000502:physiology*; D011973:Receptors, LDL / Q000235:genetics*; D014973:Xanthomatosis / Q000517:prevention & control*
D002791:Cholesterol, Dietary; D011973:Receptors, LDL; D001120:Arginine