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A model of early atherosclerosis in hamsters with moderate hypercholesterolemia (217 to 271 mg/dL) was established that was highly responsive to exogenous antioxidants. A key feature of this model was elevation of vascular oxidative stress by use of a diet deficient in nutritional antioxidants and supplemented with corn oil (10%) and cholesterol (0.2%, 0.4%, or 0.8%). After 10 weeks on the 0.4% cholesterol diet, mean plasma α-tocopherol levels declined from 5.68±0.30 to 1.27±0.15 μg/mL, while monocyte-macrophage foam cell lesions in the aortic arch, as assayed by video microscopy/image analysis of oil red O–stained histological specimens, increased from undetectable at week 0 to 60 900±5400 μm2 per specimen at week 10 (mean±SEM, n=36). α-Tocopherol or probucol administered for 10 weeks markedly suppressed LDL oxidation ex vivo and profoundly inhibited aortic foam cell formation. However, the effects of antioxidants on aortic lesions were attenuated at higher plasma cholesterol levels, although LDL oxidation ex vivo was effectively inhibited. With a plasma cholesterol level at ≈250 mg/dL, the maximum effect of α-tocopherol on lesion size reached ≈36% of control value, and the dose for half-maximal effect was ≈10 mg · kg−1 · d−1 , which resulted in a plasma α-tocopherol value of ≈20 μg/mL. Under these conditions a linear, inverse correlation of aortic lesion size and plasma α-tocopherol concentration was observed (n=68,r =−0.581,P &lt;.001). The data demonstrate that LDL oxidation is a significant component of early atherogenesis in this model but suggest that hyperlipidemia can outweigh the therapeutic effectiveness of antioxidants. The high sensitivity of aortic lesion initiation to α-tocopherol in hamsters maintained on moderately hypercholesterolemic diets depleted of endogenous antioxidants demonstrates that vascular oxidative stress can be isolated from other causative factors in an in vivo model of atherosclerosis.

Relation of Vascular Oxidative Stress, α-Tocopherol, and Hypercholesterolemia to Early Atherosclerosis in Hamsters