Antioxidants as Antiatherogens: Animal Studies

Lynch, Shaina M.; Frei, Balz

doi:10.1016/b978-0-08-057168-3.50018-7

Cited by 6 publications

(5 citation statements)

References 147 publications

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“…Unfortunately, none of the previous animal vitamin E supplementation studies has directly assessed the effect of the treatment on lipoprotein lipid peroxidation in the vessel wall. What is clear is that supplementation of animals with ␣-TOH alone generally fails to decrease atherosclerosis unless the vitamin is used at such high concentration that it causes a hypolipidemic effect (11,15,17,40).…”

Section: Discussionmentioning

confidence: 99%

Inhibition by a coantioxidant of aortic lipoprotein lipid peroxidation and atherosclerosis in apolipoprotein E and low density lipoprotein receptor gene double knockout mice

et al. 1999

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Antioxidants can inhibit atherosclerosis in animals, though it is not clear whether this is due to the inhibition of aortic lipoprotein lipid (per)oxidation. Coantioxidants inhibit radical-induced, tocopherol-mediated peroxidation of lipids in lipoproteins through elimination of tocopheroxyl radical. Here we tested the effect of the bisphenolic probucol metabolite and coantioxidant H 212/43 on atherogenesis in apolipoprotein E and low density lipoprotein (LDL) receptor gene double knockout (apoE-/-;LDLr-/-) mice, and how this related to aortic lipid (per)oxidation measured by specific HPLC analyses. Dietary supplementation with H 212/43 resulted in circulating drug levels of approximately 200 microM, increased plasma total cholesterol slightly and decreased plasma and aortic alpha-tocopherol significantly relative to age-matched control mice. Treatment with H 212/43 increased the antioxidant capacity of plasma, as indicated by prolonged inhibition of peroxyl radical-induced, ex vivo lipid peroxidation. Aortic tissue from control apoE-/-;LDLr-/- mice contained lipid hydro(pero)xides and substantial atherosclerotic lesions, both of which were decreased strongly by supplementation of the animals with H 212/43. The results show that a coantioxidant effectively inhibits in vivo lipid peroxidation and atherosclerosis in apoE-/-;LDLr-/- mice, consistent with though not proving a causal relationship between aortic lipoprotein lipid oxidation and atherosclerosis in this model of the disease.

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Section: Discussionmentioning

confidence: 99%

Inhibition by a coantioxidant of aortic lipoprotein lipid peroxidation and atherosclerosis in apolipoprotein E and low density lipoprotein receptor gene double knockout mice

et al. 1999

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“…The absence of an effect of cellular ␣-TOH on cellmediated LDL oxidation demonstrated here does not diminish the antiatherogenic potential of ␣-TOH, demonstrated in numerous epidemiological and animal studies (1,(5)(6)(7)(8). The reported beneficial effects of ␣-TOH related to atherosclerosis, which are exerted at the cellular level, include its inhibition of adhesion of monocyte to endothelial cells (41,54), stimulation of endothelial cells proliferation (53) after pretreatment with ␣-TOH, increased resistance of cultured endothelial cells to the cytotoxic effects of oxidized LDL (49), slower rates of lipid peroxidation in cells loaded with polyunsaturated fatty acids (55), and inhibition of proliferation of vascular smooth muscle cells (52).…”

Section: Discussionmentioning

confidence: 53%

“…Oxidized lipids and proteins, as well as oxidatively modified LDL, have been found in atherosclerotic lesions from both experimental animals and humans (1,(4)(5)(6). Furthermore, lipophilic antioxidants have been shown to retard the progression of dietary-induced atherosclerosis in some animal models (1,7,8). Some recent epidemiological studies suggest an association between increased intake of natural plasma antioxidants, especially vitamin E, and decreased risk of cardiovascular disease (1,9,10).…”

mentioning

confidence: 99%

α-Tocopherol supplementation of macrophages does not influence their ability to oxidize LDL

Baoutina

Dean

Jessup

1998

Journal of Lipid Research

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We have investigated the effect of ␣ -tocopherolloading of mouse peritoneal macrophages and human monocytes on their ability to oxidize human low density lipoprotein (LDL). Mouse peritoneal macrophages incorporated ␣tocopherol ( ␣ -TOH) from culture medium supplemented with the vitamin in a time-and concentration-dependent manner. Subcellular fractionation by density gradient ultracentrifugation showed that the distribution of incorporated ␣ -TOH within the cell was similar to that of free cholesterol. Most ( Ϸ 88%) of ␣ -TOH partitioned into the membrane fractions (plasma membrane Ϸ 41%, mitochondria and lysosomes Ϸ 26%, and endosomes plus endoplasmic reticulum Ϸ 21%). Cellular ␣ -TOH was stable for at least 24 h in serum-or LDLfree media whether permissive (Ham's F-10) or non-permissive (Dulbecco's minimum essential medium, DMEM) for LDL oxidation. When incubated with LDL in DMEM, ␣ -TOHpreloaded cells transferred small amounts of ␣ -TOH (approximately 1 nmol/mg LDL protein after 9 h) to the lipoprotein. However, enrichment of the cells with ␣ -TOH did not change the kinetics of oxidation of either normal or TOH-depleted LDL in Ham's F-10 medium compared with non-loaded cells, as assessed by ␣ -TOH consumption, cholesteryl ester degradation, and cholesteryl ester hydroperoxide and 7-ketocholesterol accumulation. Nor did it alter superoxide release by the cells or their ability to reduce extracellular copper(II). Similar to mouse macrophages, enrichment of human monocytes with ␣ -TOH did not change the kinetics of cell-mediated LDL oxidation. We conclude that elevated cellular levels of ␣ -TOH in mouse peritoneal macrophages and in human monocytes do not affect their ability to oxidize LDL lipids in vitro. This suggests that either cell-mediated oxidation of LDL under the conditions of this study is not dependent on cell-derived radical species or that cellular ␣ -TOH is unable to affect their formation.-Baoutina, A., R. T. Dean, and W. Jessup. ␣ -Tocopherol supplementation of macrophages does not influence their ability to oxidize LDL.

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“…In contrast to other lipid-soluble antioxidants, vitamin E at doses that fail to lower cholesterol levels has not consistently inhibited atherosclerosis in hypercholesterolemic animals [14]. It is important to note that LDL isolated from the animals was protected from oxidation ex vivo [13,15,16], implying that vitamin E was incorporated effectively into the lipoprotein.…”

Section: Vitamin E Does Not Consistently Inhibit Atherosclerosis In Amentioning

confidence: 98%

Clinical trials of vitamin E in coronary artery disease: Is it time to reconsider the low-density lipoprotein oxidation hypothesis?

Heinecke

2003

Curr Atheroscler Rep

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A wide range of structurally unrelated antioxidants inhibit atherosclerosis in animal models of hypercholesterolemia, implicating oxidation of low-density lipoprotein (LDL) in the pathogenesis of atherosclerosis. However, most prospective, randomized trials of one proposed antioxidant, vitamin E, have failed to demonstrate any reduction in cardiovascular events in humans with established coronary artery disease. Recent clinical studies suggest that vitamin E is also ineffectual in the primary prevention of atherosclerosis. These observations have led many to question the relevance of LDL oxidation to the pathogenesis of human cardiovascular disease. However, vitamin E's ineffectiveness in clinical trials might result from its failure to act as a physiologically relevant antioxidant. Indeed, vitamin E does not consistently inhibit atherosclerosis in hypercholesterolemic animals, and there is remarkably little evidence that clinically relevant doses of vitamin E result in inhibition of lipid peroxidation in vivo. Collectively, these observations indicate that there is little rationale for using vitamin E to prevent coronary artery disease in humans. They also strongly suggest that it will be critically important to establish that compounds with antioxidant activity in vitro actually prevent oxidative reactions in vivo before embarking on any new clinical trials.

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Antioxidants as Antiatherogens: Animal Studies

Cited by 6 publications

References 147 publications

Inhibition by a coantioxidant of aortic lipoprotein lipid peroxidation and atherosclerosis in apolipoprotein E and low density lipoprotein receptor gene double knockout mice

Inhibition by a coantioxidant of aortic lipoprotein lipid peroxidation and atherosclerosis in apolipoprotein E and low density lipoprotein receptor gene double knockout mice

α-Tocopherol supplementation of macrophages does not influence their ability to oxidize LDL

Clinical trials of vitamin E in coronary artery disease: Is it time to reconsider the low-density lipoprotein oxidation hypothesis?

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