Antiatherogenic effects of the antioxidant BO-653 in three different animal models

Cynshi, Osamu; Kawabe, Yojiro; Suzuki, Takahiro; Takashima, Yohei; Kaise, Hiroshi; Nakamura, Masato; Ohba, Yasuhiro; Kato, Yoshiaki; Tamura, Kunio; Hayasaka, Akira; Higashida, Atsuko; Sakaguchi, Hisashi; Takeya, Motohiro; Takahashi, Kiyoshi; Inoue, Kenji; Noguchi, Noriko; Niki, Etsuo; Kodama, Tatsuhiko

doi:10.1073/pnas.95.17.10123

Cited by 87 publications

(50 citation statements)

References 35 publications

(25 reference statements)

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“…However, it is not immediately obvious how lipid lowering alone could explain the observed caudal increase in inhibition of atherosclerosis (Table I) or the increase in lesion size in the aortic origin by probucol. 25,26 Several explanations have been proposed for the proatherogenic activity of probucol in the aortic root, including the lowering of HDL, 24,26 probucol toxicity, increased plasma fibrinogen, and decreased plasma lipoprotein lipase activities. 26 However, in the present study, probucol did not lower HDL.…”

Section: Discussionmentioning

confidence: 99%

“…Lesion development in apoEϪ/Ϫ mice is observed first in the aortic root and later distally along the aortic tree. 35 Hence, the proatherogenic [22][23][24] and antiatherogenic activity of probucol (this study) at the most proximal and distal sites, respectively, could be explained if lesions existed in the aortic origin but not along the transverse, descending, and abdominal aorta before the intervention. The treatment period of our study was sufficiently long to allow growth of lesions at all sites studied.…”

Section: Discussionmentioning

confidence: 99%

“…20 It is also ineffective in reducing established lesions in mature, LDL receptor-deficient rabbits 21 and nonhuman primates. 14 Furthermore, probucol promotes atherosclerosis in the aortic origin in LDL receptor- [22][23][24] and apolipoprotein E-deficient (apoEϪ/Ϫ) mice 25,26 for reasons presently unknown.…”

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confidence: 99%

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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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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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

Witting

Pettersson

Letters

et al. 2000

ATVB

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“…26 Probucol, which reduces plasma HDL, has been shown to interfere with the cellapolipoprotein interaction to inhibit the generation of HDL in vitro 7,8 and in vitro 9 and to induce tissue cholesterol accumulation in a certain strain of mouse. 27 Tangier disease was shown to be caused by the impairment of the apolipoproteincell interaction to generate HDL, 10,11 and the causative mutations were identified in the genes of ABC1 for Tangier disease and other types of familial HDL deficiency. [12][13][14][15][16][17] Thus, the apolipoprotein-cell interaction was shown to be a major source of plasma HDL.…”

Section: Discussionmentioning

confidence: 99%

“…31 However, under certain conditions, opposite observations have been reported; in mice, probucol has been shown to induce the deposition of cholesterol in tissues. 27,32 The controversy may be related to the balance between the antioxidative and anti-inflammatory actions of the drug and its strong HDL-reducing effect. 33 Therefore, the effect of probucol on tissue cholesterol accumulation may have to be evaluated carefully.…”

Section: Tomimoto Et Al Effect Of Probucol In Lcat-deficient Micementioning

confidence: 99%

Effect of Probucol in Lecithin-Cholesterol Acyltransferase–Deficient Mice

Tomimoto

Tsujita²,

Okazaki

et al. 2001

ATVB

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Abstract-Cellular cholesterol release takes place by at least 2 distinct mechanisms: the lecithin-cholesterol acyltransferase (LCAT)-driven net efflux by cholesterol diffusion and the generation of high density lipoprotein (HDL) with cellular cholesterol and phospholipid on the cell-apolipoprotein interaction. Therefore, LCAT deficiency impairs the former pathway, and the latter can be inhibited by probucol, which interferes with the apolipoprotein-cell interaction. Hence, probucol was given to the LCAT-deficient mice in the attempt to suppress both of these pathways. The mice were fed low (0.2%) and high (1.2%) cholesterol diets containing 0.5% probucol for 2 weeks. LCAT deficiency and probucol markedly decreased plasma HDL, and the effects were synergistic. Tissue cholesterol content was lower in the adrenal glands and ovaries in the LCAT-deficient mice and in the probucol-treated mice, suggesting that HDL is a main cholesterol provider for these organs. It was also moderately decreased in the spleen of the low cholesterol-fed female mice and in the thyroid gland of the low cholesterol-fed male mice. On the other hand, the esterified cholesterol content in the liver was substantially increased by the probucol treatment with a high cholesterol diet in the LCAT-deficient mice but not in the wild-type mice. Among the groups, there was no significant difference in the tissue cholesterol levels in other organs, such as the liver, spleen, thymus, brain, erythrocytes, thyroid gland, testis, and aorta, resulting from either LCAT deficiency or probucol. Thus, the apolipoprotein-mediated mechanism plays a significant role in the export of cellular cholesterol in the liver, indicating that the liver is a major site of the HDL assembly. Otherwise, tissue cholesterol homeostasis can largely be maintained in mice even when the assembly of new HDL is inhibited by probucol in the absence of LCAT. Nonspecific diffusion of cholesterol perhaps adequately maintains the homeostasis in the experimental condition. Key Words: high density lipoproteins Ⅲ lecithin-cholesterol acyltransferase Ⅲ cholesterol efflux Ⅲ cholesterol homeostasis Ⅲ probucol H igh density lipoprotein (HDL) is given a key role in the hypothesis of a cholesterol transport pathway from the peripheral tissues to the liver. The physiological importance of this transport system lies in the fact that cholesterol is not catabolized in the peripheral tissues and must be transported to its catabolic sites, mainly, the liver (for its conversion to bile acids) and, to a much lesser extent, the steroidogenic cells. The hypothesis is extended to the "antiatherogenic" function of this transport pathway, which is based on experimental data indicating that HDL removes the accumulated cholesterol from the cells in vitro 1 and epidemiological evidence indicating that the plasma HDL level is negatively correlated with the risk of coronary heart disease. 2 The most critical biological step of this pathway is the release of cholesterol from the cells. At least 2 distinct mechanisms a...

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Antihyperlipidemic Agents

Sierra

2003

Burger's Medicinal Chemistry and Drug Discovery

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Coronary heart disease (CHD) is the leading cause of morbidity and mortality in developed nations and atherosclerotic cardiovascular disease accounts for approximately half of all deaths attributed to CHD. Dyslipidemia, including hypercholesterolemia, hypertriglyceridemia, and hypoalphalipoproteinemia, is a major risk factor for CHD. Clinical studies have demonstrated the link between elevated serum cholesterol and coronary disease. Randomized controlled studies investigating the benefit of therapies that lower serum levels of low density lipoprotein cholesterol have demonstrated improvements in coronary morbidity and mortality in patients with or without diagnosed CHD. Furthermore, data are accumulating based on the VA‐HIT trial and several other ongoing trials with fibrates that the treatment of high serum triglycerides and low concentrations of high density lipoprotein cholesterol can also lead to improvements in coronary morbidity and mortality. This review discusses the development of the HMG‐CoA reductase inhibitors and how they have, thanks to their excellent efficacy and good safety profile, revolutionized the clinical management of hypercholesterolemia. Other treatments such as fibrates, bile acid sequestrants, cholesterol absorption inhibitors, and nicotinic acid derivatives as well as new emerging treatments are also discussed.

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Antiatherogenic effects of the antioxidant BO-653 in three different animal models

Cited by 87 publications

References 35 publications

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

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

Effect of Probucol in Lecithin-Cholesterol Acyltransferase–Deficient Mice

Antihyperlipidemic Agents

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