Dissociation of atherogenesis from aortic accumulation of lipid hydro(pero)xides in Watanabe heritable hyperlipidemic rabbits

Abstract

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 α-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 α-tocopherol and cholesterol. Together, these results suggest that aortic accumulation of LO(O)H is not required for, nor is α-tocopherol depleted during, the initiation and progression of atherogenesis in WHHL rabbits.

Probucol Promotes Functional Reendothelialization in Balloon-Injured Rabbit Aortas

“…20 Also, although probucol decreases aortic oxysterols 28 and thiobarbituric acid-reactive substances 10 in balloon-injured rabbits, the precise role of these lipid oxidation products in vascular disease remains unclear. 24 More importantly, we show here that protection by probucol was not associated consistently with a decrease in oxidized lipids, whether expressed per protein or parent lipid. Therefore, inhibition of aortic lipoprotein lipid oxidation does not appear to explain why probucol inhibits intimal proliferation in the animal model used, consistent with the inability of probucol to decrease oxidation-specific epitopes in monkeys 18 and Watanabe heritable hyperlipidemic rabbits 29 at aortic sites at which probucol decreases lesion.…”

“…At 6 weeks, aorta was harvested. Segments for biochemical analyses were perfused, homogenized, and analyzed by high-performance liquid chromatography 24 ; those for histology were pressure-perfused with formalin, stored in 70% (vol/vol) ethanol, and then embedded in paraffin.…”

Therapeutic effects of quercetin against bisphenol A induced testicular damage in male Sprague Dawley rats

“…rabbits, BPA intravenous administration for 12 weeks caused an increase in plasma total cholesterol and triglycerides [Witting et al 1999]. BPA acts as a ligand for the estrogen receptor and activates intracellular pathways in the tissues similar to estrogen.…”

Site-Specific Antiatherogenic Effect of Probucol in Apolipoprotein E–Deficient Mice

“…We have shown recently that in LDL receptor-deficient rabbits, the accumulation of lipoprotein LOOH and CE-OH is dissociated from atherosclerosis. 39 Future studies will have to address how important aortic lipoprotein lipid oxidation is as a cause of atherosclerosis in apoEϪ/Ϫ mice. Interestingly, in humans, probucol prevented restenosis after coronary angioplasty, whereas an antioxidant multivitamin cocktail was without benefit and reversed the effect of probucol.…”