The relationship between the degree of dietary-induced hypercholesterolemia in the rabbit and atherosclerotic lesion formation.
A biochemical, histologic and morphometric evaluation of spontaneous, diet-induced (thoracic aorta) and injury-induced (iliac-femoral) atherosclerotic lesions was performed in rabbits maintained on varying levels of dietary cholesterol. Rabbits were meal-fed a 3% peanut oil, 3% coconut oil diet containing 0%, 0.1%, 0.25%, 0.5%, 1.0%, 1.5% or 2.0% cholesterol for 9 weeks. Plasma total cholesterol exposure (area under cholesterol-time curve (TC-AUC)) increased diet-dependently over the course of the study. VLDL and LDL cholesterol (VLDL-C, LDL-C) comprised 41% and 55%, respectively, of the plasma total cholesterol at cholesterol levels > 700 mg/dl (TC-AUC > 31,868 mg day/dl) and both VLDL-C and LDL-C were linearly related to TC-AUC (r = 0.98). Plasma TC-AUC was linearly related to thoracic aortic cholesteryl ester (CE) content (r = 0.74) and thoracic aortic lesion coverage (r = 0.66). In the injury-induced iliac-femoral lesion, plasma TC-AUC was linearly related to both iliac-femoral CE content (r = 0.80) and macrophage/lesion ratio (r = 0.64). At plasma cholesterol levels greater than 700 mg/dl, CE content of the iliac-femoral lesion ranged from 35 to 69 micrograms/mg dry defatted tissue, > 75% of the lesions were fibrofoamy in nature and macrophage/lesion area ratio was 0.46 to 0.55 while lesion area remained constant. VLDL-C and LDL-C were highly correlated with the CE content of both thoracic and iliac-femoral lesions, thoracic aortic lesion coverage and macrophage/lesion area ratio (r = 0.86-0.99). We conclude that the composition, extent and type of atherosclerotic lesion induced in rabbits is dependent upon the overall plasma cholesterol exposure, VLDL and LDL cholesterol content and whether lesions are induced by diet alone or both diet and chronic endothelial injury. In addition, various stages of atherosclerotic lesion formation can be replicated in the rabbit by titrating the animal's overall plasma cholesterol exposure.
Bocan
T M
TM
Department of Pharmacology, Parke-Davis Pharmaceutical Research Division, Warner-Lambert Company, Ann Arbor, MI 48105.
Mueller
S B
SB
Mazur
M J
MJ
Uhlendorf
P D
PD
Brown
E Q
EQ
Kieft
K A
KA
D000818:Animals; D001013:Aorta, Thoracic / Q000473:pathology; D001161:Arteriosclerosis / Q000097:blood / Q000150:complications / Q000473:pathology*; D002784:Cholesterol / Q000378:metabolism; D002791:Cholesterol, Dietary / Q000008:administration & dosage; D005263:Femoral Artery / Q000473:pathology; D006937:Hypercholesterolemia / Q000150:complications* / Q000378:metabolism; D007083:Iliac Artery / Q000473:pathology; D008099:Liver / Q000378:metabolism; D008297:Male; D011817:Rabbits
D002791:Cholesterol, Dietary; D002784:Cholesterol