title: Relation of vascular oxidative stress, alpha-tocopherol, and hypercholesterolemia to early atherosclerosis in hamsters.
abstract: 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 alpha-tocopherol levels declined from 5.68 +/- 0.30 to 1.27 +/- 0.15 micrograms/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 microns 2 per specimen at week 10 (mean +/- SEM, n = 36). alpha-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 approximately 250 mg/dL, the maximum effect of alpha-tocopherol on lesion size reached approximately 36% of control value, and the dose for half-maximal effect was approximately 10 mg.kg-1.d-1, which resulted in a plasma alpha-tocopherol value of approximately 20 micrograms/mL. Under these conditions a linear, inverse correlation of aortic lesion size and plasma alpha-tocopherol concentration was observed (n = 68, r = -0.581, P < .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 alpha-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.
authors.affiliation: Department of Metabolic Diseases, Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, NJ 08543-4000, USA.
authors.forename: R A
authors.initials: RA
authors.lastname: Parker
authors.forename: T
authors.initials: T
authors.lastname: Sabrah
authors.forename: M
authors.initials: M
authors.lastname: Cap
authors.forename: B T
authors.initials: BT
authors.lastname: Gill
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000008:administration & dosage; D001011:Aorta / Q000378:metabolism* / Q000473:pathology; D001161:Arteriosclerosis / Q000209:etiology*; D003314:Corn Oil; D006224:Cricetinae; D004036:Diet, Atherogenic; D004305:Dose-Response Relationship, Drug; D005526:Food, Formulated; D006937:Hypercholesterolemia / Q000150:complications*; D008077:Lipoproteins, LDL / Q000378:metabolism; D008297:Male; D008647:Mesocricetus; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D011341:Probucol / Q000494:pharmacology; D014810:Vitamin E / Q000494:pharmacology*
chemical_list: D000975:Antioxidants; D008077:Lipoproteins, LDL; D014810:Vitamin E; D003314:Corn Oil; D011341:Probucol