Comparison of the effects of alpha-tocopherol, ubiquinone-10 and probucol at therapeutic doses on atherosclerosis in WHHL rabbits.
Oxidative modification of lipoproteins may trigger and maintain atherogenesis. We compared the effects of different antioxidants (alpha-tocopherol, probucol, ubiquinone-10) at doses similar to those used in humans in Watanabe Heritable Hyperlipidemic (WHHL) rabbits for 12 months. Aortic lesions were analyzed for their extent and cellular composition of lesions, mean thickness of fibrous caps and density of smooth muscle cells therein, content of antioxidants, non-oxidized and oxidized lipids. Compared to controls, probucol significantly lowered the extent and macrophage content of lesions and increased the existence and smooth muscle cell density of fibrous caps. alpha-Tocopherol supplementation increased the aortic content of vitamin E, but had no decreasing effect on either the accumulation of macrophage-specific antigen in the aorta or lesion size. Nevertheless, both probucol and alpha-tocopherol significantly decreased in vitro LDL oxidizability, measured under typically strong oxidative conditions. Ubiquinone-10 supplement increased lesion size and the fraction of lesions containing fibrous caps; however, LDL oxidizability remained unaffected by ubiquinone-10 treatment. None of the antioxidants tested lowered oxidized lipids within aortic tissue; however, long-term treatment with probucol provided the most effective anti-atherosclerotic effect, while alpha-tocopherol may be pro-atherogenic and ubiquinone-10 exerts ambivalent effects. Our data suggest that (i) widely used oxidation measures, such as ex-vivo LDL oxidizability, do not reflect the degree of atherosclerosis; and (ii) long-term beneficial effects of relatively low doses of antioxidants may be outweighed by high levels of plasma cholesterol in WHHL rabbits.
Bräsen
Jan Hinrich
JH
HELIOS Klinikum-Berlin, Franz Volhard Clinic at the Max Delbrück Center for Molecular Medicine, Medical Faculty of the Charité, Humboldt University, Wiltbergstr. 50, 13125 Berlin, Germany. braesen@fvk-berlin.de
Koenig
Kai
K
Bach
Heiko
H
Kontush
Anatol
A
Heinle
Helmut
H
Witting
Paul K
PK
Ylä-Herttuala
Seppo
S
Stocker
Roland
R
Beisiegel
Ulrike
U
D000818:Animals; D000975:Antioxidants / Q000008:administration & dosage* / Q000493:pharmacokinetics; D001011:Aorta / Q000378:metabolism / Q000473:pathology; D001161:Arteriosclerosis / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D003067:Coenzymes; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D008055:Lipids / Q000097:blood; D008077:Lipoproteins, LDL / Q000378:metabolism; D008297:Male; D011341:Probucol / Q000008:administration & dosage* / Q000493:pharmacokinetics; D011817:Rabbits; D014451:Ubiquinone / Q000008:administration & dosage* / Q000031:analogs & derivatives* / Q000378:metabolism / Q000493:pharmacokinetics; D014810:Vitamin E / Q000378:metabolism; D024502:alpha-Tocopherol / Q000008:administration & dosage* / Q000493:pharmacokinetics
D000975:Antioxidants; D003067:Coenzymes; D008055:Lipids; D008077:Lipoproteins, LDL; C099252:oxidized low density lipoprotein; D014451:Ubiquinone; D014810:Vitamin E; C024989:coenzyme Q10; D024502:alpha-Tocopherol; C025204:Ubiquinone Q2; D011341:Probucol