Inhibition by a coantioxidant of aortic lipoprotein lipid peroxidation and atherosclerosis in apolipoprotein E and low density lipoprotein receptor gene double knockout mice

• Published in: The FASEB journal Vol. 13; no. 6; p. 667
• Main Authors: Witting, P K, Pettersson, K, Ostlund-Lindqvist, A M, Westerlund, C, Eriksson, A W, Stocker, R
• Format: Journal Article
• Language: English
• Published: United States 01.04.1999
• Subjects: Animals; Antioxidants - pharmacology; Aorta - drug effects; Apolipoproteins E - genetics; Arteriosclerosis - drug therapy; Benzhydryl Compounds; Cholesterol - blood; Lipid Peroxidation - drug effects; Male; Mice; Mice, Knockout; Phenols - blood; Phenols - pharmacology; Probucol - metabolism; Receptors, Lipoprotein - genetics; Triglycerides - blood
• ISSN: 0892-6638
• DOI: 10.1096/fasebj.13.6.667

Antioxidants can inhibit atherosclerosis in animals, though it is not clear whether this is due to the inhibition of aortic lipoprotein lipid (per)oxidation. Coantioxidants inhibit radical-induced, tocopherol-mediated peroxidation of lipids in lipoproteins through elimination of tocopheroxyl radical. Here we tested the effect of the bisphenolic probucol metabolite and coantioxidant H 212/43 on atherogenesis in apolipoprotein E and low density lipoprotein (LDL) receptor gene double knockout (apoE-/-;LDLr-/-) mice, and how this related to aortic lipid (per)oxidation measured by specific HPLC analyses. Dietary supplementation with H 212/43 resulted in circulating drug levels of approximately 200 microM, increased plasma total cholesterol slightly and decreased plasma and aortic alpha-tocopherol significantly relative to age-matched control mice. Treatment with H 212/43 increased the antioxidant capacity of plasma, as indicated by prolonged inhibition of peroxyl radical-induced, ex vivo lipid peroxidation. Aortic tissue from control apoE-/-;LDLr-/- mice contained lipid hydro(pero)xides and substantial atherosclerotic lesions, both of which were decreased strongly by supplementation of the animals with H 212/43. The results show that a coantioxidant effectively inhibits in vivo lipid peroxidation and atherosclerosis in apoE-/-;LDLr-/- mice, consistent with though not proving a causal relationship between aortic lipoprotein lipid oxidation and atherosclerosis in this model of the disease.