Dissociation of atherogenesis from aortic accumulation of lipid hydro(pero)xides in Watanabe heritable hyperlipidemic rabbits.
Antioxidants can inhibit atherosclerosis, but it is unclear how inhibition of intimal lipid oxidation relates to atherogenesis. Here we tested the effect of probucol and its metabolite bisphenol on aortic lipid (per)oxidation and atherogenesis in Watanabe heritable hyperlipidemic (WHHL) rabbits. LDL and aortas from rabbits fed probucol contained bisphenol at concentrations comparable to those in bisphenol-treated animals. Bisphenol treatment increased plasma cholesterol slightly, and plasma and aortic alpha-tocopherol more substantially; these parameters were unaffected by probucol. Bisphenol and probucol treatment both enhanced the resistance of circulating LDL to peroxyl radical-induced lipid peroxidation; this was due to bisphenol, not probucol. Only probucol enhanced LDL's resistance to Cu(2+)-induced oxidation. Both bisphenol and probucol treatment strongly inhibited aortic accumulation of hydroperoxides and hydroxides of cholesteryl esters and triglycerides [LO(O)H]. Despite this, however, probucol had a modestly significant effect on the extent of lesion formation; bisphenol had no inhibitory effect. In addition, the extent of atherosclerosis did not correlate with amounts of aortic LO(O)H present, but, as expected, it did correlate with aortic alpha-tocopherol and cholesterol. Together, these results suggest that aortic accumulation of LO(O)H is not required for, nor is alpha-tocopherol depleted during, the initiation and progression of atherogenesis in WHHL rabbits.
Witting
P
P
Biochemistry Group, The Heart Research Institute, Camperdown, New South Wales 2050, Australia Astra Hässle, S-43183 Mölndal, Sweden.
Pettersson
K
K
Ostlund-Lindqvist
A M
AM
Westerlund
C
C
Wâgberg
M
M
Stocker
R
R
D000818:Animals; D001011:Aorta / Q000378:metabolism*; D001161:Arteriosclerosis / Q000209:etiology*; D006949:Hyperlipidemias / Q000150:complications / Q000378:metabolism*; D015227:Lipid Peroxidation / Q000187:drug effects; D008055:Lipids / Q000097:blood; D008077:Lipoproteins, LDL / Q000378:metabolism; D008297:Male; D010084:Oxidation-Reduction; D011341:Probucol / Q000494:pharmacology; D011817:Rabbits
D008055:Lipids; D008077:Lipoproteins, LDL; D011341:Probucol