Probucol treatment affects the cellular composition but not anti-oxidized low density lipoprotein immunoreactivity of plaques from Watanabe heritable hyperlipidemic rabbits.

O’Brien, Kevin D.; Nagano, Yutaka; Gown, Allen M.; Kita, Toru; Chait, Alan

doi:10.1161/01.atv.11.3.751

Cited by 69 publications

(26 citation statements)

References 19 publications

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“…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. However, our results do not rule out the possibility that probucol inhibits oxidative events unrelated to lipoprotein oxidation.…”

Section: Discussionmentioning

confidence: 78%

Probucol Promotes Functional Reendothelialization in Balloon-Injured Rabbit Aortas

et al. 2003

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Background-Probucol remains the only conventional drug that reduces restenosis after coronary angioplasty. Apart from its weak cholesterol-lowering effect, probucol has antioxidant properties, but it remains unclear how this drug inhibits restenosis. Methods and Results-Aortic balloon-injured New Zealand White rabbits were fed 2% (wt/wt) cholesterol-enriched or normal chow, with 0.75% (wt/wt) probucol (P) or without (controls, C) for 6 weeks. Endothelial denudation of the abdominal aorta was performed at week 3 with a 3F Fogarty embolectomy catheter. The arteries were harvested after week 6 and analyzed for histology, lipids and antioxidants, and endothelial regeneration and function. Probucol significantly decreased aortic intima-to-media ratio (cholesterol-fed: C, 1.10Ϯ0.08 versus P, 0.70Ϯ0.10; normal: C, 0.89Ϯ0.02 versus P, 0.83Ϯ0.05; PϽ0.05) and the numbers of proliferating intimal smooth muscle cells and lowered serum cholesterol without altering the proportion of aortic lipids that was oxidized. Probucol promoted endothelial regeneration in the injured aorta in cholesterol-fed rabbits (25% increase in reendothelialization, PϽ0.05) and in those on normal chow (37% increase, PϽ0.01). This was associated with both improved endothelial function as assessed by enhanced aortic ring relaxation and cGMP production in response to acetylcholine and decreased intimal thickening. Conclusions-Probucol inhibits intimal thickening in balloon-damaged arteries of rabbits by promoting the regeneration of functional endothelium, without affecting the proportion of aortic lipids that was oxidized. This novel in vivo finding helps explain how probucol inhibits restenosis after coronary angioplasty and highlights potential new targets for therapeutic intervention.

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Section: Discussionmentioning

confidence: 78%

Probucol Promotes Functional Reendothelialization in Balloon-Injured Rabbit Aortas

et al. 2003

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“…A previous study had shown that probucol decreased the content of oxysterols (that are secondary lipid oxidation products) in rabbit aortas. 37 In contrast, O'Brien et al 38 did not observe a decrease in oxidized LDL in plaques of LDL receptor-deficient rabbits fed probucol. However, in that study, the tissue sections used were fixed, and this process could have caused inadvertent lipid oxidation (see Methods).…”

Section: Discussionmentioning

confidence: 90%

“…15,43 Because vascular cell adhesion molecule-1 expression is correlated with and can contribute to the entry of macrophages into the intima, 44 its downregulation by probucol could attenuate atherosclerosis by decreasing the intimal accumulation of macrophages. 38 The expression of adhesion molecules 44 and the distribution of inflammatory cells within the vessel wall 45 are affected by arterial blood flow, so that these local differences in hemodynamic factors could be relevant.…”

Section: Discussionmentioning

confidence: 99%

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

Witting

Pettersson

Letters

et al. 2000

ATVB

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Abstract-The lipid-lowering antioxidant probucol can inhibit atherosclerosis in animals and restenosis in humans.However, probucol has been shown to promote atherosclerosis in the aortic root of apolipoprotein E-deficient (apoEϪ/Ϫ) mice. In the current study, we examined the effects of probucol on both lesion formation at 4 sites along the aorta and lipoprotein oxidation in the plasma and aortas of apoEϪ/Ϫ mice receiving a diet containing 21.2% (wt/wt) fat and 0.15% (wt/wt) cholesterol without or with 1% (wt/wt) probucol. After 6 months, controls had developed lesions at all sites investigated. Lesion development was strongly (Pϭ0.0001) affected by probucol, but this effect was not uniform: lesion size was increased in the aortic root but significantly decreased in the arch, the descending thoracic aorta, and proximal abdominal aorta. Plasma and aortas of probucol-treated mice contained high concentrations of probucol and its metabolites (bisphenol and diphenoquinone); increased vitamin C; markedly decreased very low density lipoprotein (but not low density lipoprotein and high density lipoprotein); and decreased cholesterol, cholesteryl esters, triglycerides, vitamin E, and oxidized lipids compared with controls. Interestingly, probucol treatment did not decrease the proportion of aortic lipids that were oxidized. Plasma vitamin C and bisphenol, but not probucol, protected plasma lipids from ex vivo oxidation by peroxyl radicals. These results show that as in other species, probucol can inhibit lesion formation in most parts of the aorta of apoEϪ/Ϫ mice. This effect may involve lipid oxidation-independent mechanisms localized within the vessel wall as well as lipid lowering.

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“…51 In primates, rabbits, and mice, probucol appears to have distinctive effects on the cellularity of lesions by decreasing the population of macrophage foam cells while increasing the prominence of smooth muscle cells and extracellular matrix deposition. 52,53 In numerous studies of rabbits, probucol reduced the extent of atherosclerosis and appeared to be superior to other antioxidants such as vitamin E or probucol analogues. 22,40,54,55 This result suggested either that the effects of antioxidants on atherosclerosis need to surpass a threshold level and that probucol is more effective than other antioxidants or that there are distinct biological effects of probucol.…”

Section: Discussionmentioning

confidence: 99%

Probucol Enhances Selective Uptake of HDL-Associated Cholesteryl Esters In Vitro by a Scavenger Receptor B-I–Dependent Mechanism

Rinninger

Wang

Ramakrishnan

et al. 1999

ATVB

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Abstract-Recently, the class B, type I scavenger receptor (SR-BI) has been shown to mediate the selective uptake of high density lipoprotein (HDL) cholesteryl esters (CEs), ie, lipid uptake independent of HDL holoparticle uptake. In vivo, this selective uptake delivers CEs to the liver for excretion and to steroidogenic tissues for hormone synthesis. Probucol, a hydrophobic antioxidant drug, lowers plasma cholesterol in humans and rodents and may inhibit progression of atherosclerosis and postangioplasty restenosis. In this study, the effect of probucol on HDL selective CE uptake was investigated in mice and in cells expressing SR-BI. Probucol feeding lowered plasma HDL cholesterol and markedly increased selective CE uptake from HDL in the liver and adrenal glands. However, probucol did not alter SR-BI protein levels in membranes from these organs. When incubated with control Chinese hamster ovary (CHO) cells, HDL isolated from probucol-treated mice (P-HDL) and HDL from control mice (C-HDL) showed similar low selective uptake of CEs. However, when incubated with SR-BI-transfected CHO cells, P-HDL showed a 2-fold increase in selective uptake compared with C-HDL. In an adrenal cell line (Y1-BS1), which expresses SR-BI in an adrenocorticotropic hormone-inducible manner, P-HDL showed significantly greater selective CE uptake than did C-HDL, and the differential response was amplified by adrenocorticotropic hormone treatment. In contrast to P-HDL, incorporation of this compound into HDL in vitro did not result in stimulation of selective CE uptake by SR-BI-transfected CHO cells, even though a significant mass of probucol could be detected in the HDL preparation. The specific interaction of P-HDL with SR-BI in cell culture could be observed after only 24 hours of probucol feeding, when there were minimal changes in HDL size and composition. Thus, probucol or one of its metabolites increases selective CE uptake in vivo by modifying HDL in a way that causes enhanced interaction with SR-BI. The increased interaction of P-HDL with SR-BI in the liver and arterial wall may be partly responsible for the effects of probucol on atherosclerosis and restenosis. Key Words: HDL Ⅲ selective uptake Ⅲ scavenger receptor BI Ⅲ probucol P lasma HDL plays a critical role in cholesterol metabolism in vivo. HDL removes cholesterol from cells in culture and from peripheral tissues. 1,2 After cholesterol esterification, HDL-associated cholesteryl esters (CEs) can be transferred to other lipoprotein fractions by cholesteryl ester transfer protein (CETP) in some species 3 or directly delivered to tissues. 1 In rats, HDL-associated CEs can be taken up by the liver and steroidogenic tissues without parallel uptake of HDL apolipoproteins, and this metabolic pathway has been designated the selective CE uptake pathway. 4 This selective uptake delivers CEs to steroidogenic tissues for hormone synthesis and to the liver, where HDL-derived cholesterol is either secreted into the bile, used for bile acid synthesis, or secreted in newly synthesized lipo...

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Probucol treatment affects the cellular composition but not anti-oxidized low density lipoprotein immunoreactivity of plaques from Watanabe heritable hyperlipidemic rabbits.

Cited by 69 publications

References 19 publications

Probucol Promotes Functional Reendothelialization in Balloon-Injured Rabbit Aortas

Probucol Promotes Functional Reendothelialization in Balloon-Injured Rabbit Aortas

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

Probucol Enhances Selective Uptake of HDL-Associated Cholesteryl Esters In Vitro by a Scavenger Receptor B-I–Dependent Mechanism

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