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) ather osclerotic lesions was performed in rabbits maintained on varying leve ls of dietary cholesterol. Rabbits were meal-fed a 3% peanut oil, 3% c oconut oil diet containing 0%, 0.1%, 0.25%, 0.5%, 1.0%, 1.5% or 2.0% c holesterol for 9 weeks. Plasma total cholesterol exposure (area under cholesterol-time curve (TC-AUC)) increased diet-dependently over the c ourse of the study. VLDL and LDL cholesterol (VLDL-C, LDL-C) comprised 41% and 55%, respectively, of the plasma total cholesterol at cholest erol levels > 700 mg/dl (TC-AUC > 31 868 mg day/dl) and both VLDL-C an d 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 bo th iliac-femoral CE content (r = 0.80) and macrophage/lesion ratio (r = 0.64). At plasma cholesterol levels greater than 700 mg/dl, CE conte nt of the iliac-femoral lesion ranged from 35 to 69 mug/mg dry defatte d tissue, >75% of the lesions were fibrofoamy in nature and macrophage /lesion area ratio was 0.46 to 0.55 while lesion area remained constan t. VLDL-C and LDL-C were highly correlated with the CE content of both thoracic and iliac-femoral lesions, thoracic aortic lesion coverage a nd macrophage/lesion area ratio (r = 0.86-0.99). We conclude that the composition, extent and type of atherosclerotic lesion induced in rabb its is dependent upon the overall plasma cholesterol exposure, VLDL an d LDL cholesterol content and whether lesions are induced by diet alon e or both diet and chronic endothelial injury. In addition, various st ages of atherosclerotic lesion formation can be replicated in the rabb it by titrating the animal's overall plasma cholesterol exposure.