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 eff ect 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 incr eased plasma cholesterol slightly, and plasma and aortic a-tocopherol more substantially; these parameters were unaffected by probucol. Bisphenol and probucol treatment both enhanced the resistance of circulating LDL to perox yl radical-induced lipid peroxidation; this was due to bisphenol, not probu col. Only probucol enhanced LDL's resistance to CU2+- induced oxidation. Bo th bisphenol and probucol treatment strongly inhibited aortic accumulation of hydroperoxides and hydroxides of cholesteryl esters and triglycerides [L O(O)H]. Despite this, however, probucol had a modestly significant effect o n the extent of lesion formation; bisphenol had no inhibitory effect. In ad dition, the extent of atherosclerosis did not correlate with amounts of aor tic LO(O)H present, but, as expected, it did correlate with aortic a-tocoph erol and cholesterol. Together, these results suggest that aortic accumulat ion of LO(O)H is not required for, nor is a-tocopherol depleted during, the initiation and progression of atherogenesis in WHHL rabbits.