Coenzyme Q(10) supplementation inhibits aortic lipid oxidation but fails to attenuate intimal thickening in balloon-injured New Zealand white rabbits.
ABSTRACT Oxidized lipoproteins are implicated in atherosclerosis, and some antioxidants attenuate the disease in animals. Coenzyme Q(10) (CoQ(10)) in its reduced form, ubiquinol-10, effectively inhibits lipoprotein oxidation in vitro and in vivo; CoQ(10) supplements also inhibit atherosclerosis in apolipoprotein E gene knockout (apoE-/-) mice. Here we tested the effect of dietary CoQ(10) supplements on intimal proliferation and lipoprotein lipid oxidation in balloon-injured, hypercholesterolemic rabbits. Compared to nonsupplemented chow, CoQ(10) supplementation (0.5% and 1.0%, w/w) significantly increased the plasma concentration of CoQ(10) and the resistance of plasma lipids to ex vivo oxidation. CoQ(10) supplements also increased the content of CoQ(10) in the aorta and liver, but not in the brain, skeletal muscle, kidney, and heart. Surprisingly, CoQ(10) supplementation at 1% increased the aortic concentrations of all lipids, particularly triacylglycerols, although it significantly inhibited the proportion of triacylglycerols present as hydroperoxides by > 80%. The observed increase in vessel wall lipid content was reflected in elevated plasma concentrations of cholesterol, cholesteryl esters and triacylglycerols, and hepatic levels of mRNA for 3-hydroxy-3-methylglutaryl-coenzyme A reductase. CoQ(10) supplements did not attenuate lesion formation, assessed by the intima-to-media ratio of injured aortic vessels. Thus, like in apoE-/- mice, a high dose of supplemented CoQ(10) inhibits lipid oxidation in the artery wall of balloon-injured, hypercholesterolemic rabbits. However, unlike its antiatherosclerosis activity in the mice, CoQ(10) does not inhibit intimal hyperplasia in rabbits, thereby dissociating this disease process from lipid oxidation in the vessel wall.
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ABSTRACT: This article reviews our current understanding of the mechanisms of low-density lipoprotein (LDL) oxidation and the potential role of oxidized lipoproteins in atherosclerosis. Studies in hypercholesterolemic animal models indicate that oxidation of LDL is likely to play an important role in atherogenesis. Epidemiological investigations further suggest that the dietary intake of antioxidants is inversely associated with the risk of vascular disease, suggesting that oxidized LDL may be important in human atherosclerosis. By activating inflammatory events, oxidized lipoproteins may contribute to all stages of the atherosclerotic process. Lipoprotein oxidation is promoted by several different systems in vitro, including free and protein-bound metal ions, thiols, reactive oxygen intermediates, lipoxygenase, peroxynitrite, and myeloperoxidase. Intracellular proteins that bind iron or regulate iron metabolism might also play an important role. The physiologically relevant pathways have yet to be identified, however. We assess recent findings on the effects of antioxidants in vivo and suggest potential strategies for inhibiting oxidation in the vessel wall.Free Radical Biology and Medicine 02/1996; 20(5):707-27. · 5.27 Impact Factor
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ABSTRACT: Excess vascular oxidative stress and the local formation of oxidized LDL (ox-LDL) have been implicated in the development of impaired endothelium-dependent arterial relaxation in hypercholesterolemia and atherosclerosis. Dietary antioxidants limit LDL oxidation in vitro and treatment of cholesterol-fed rabbits with dietary antioxidants preserves endothelium-derived relaxing factor (EDRF) action. To investigate the mechanism(s) responsible for these observations, we examined EDRF action, vascular oxidative stress, and antioxidant protection in male New Zealand White rabbits using four dietary treatments. Animals consumed standard chow (chow group) or chow supplemented with: (a) 0.5% cholesterol (0.5% cholesterol group); (b) 1% cholesterol (1% cholesterol group); or (c) 1% cholesterol and 1% probucol (probucol group). After 28 d of dietary treatment, segments of thoracic aorta from the 0.5 and 1% cholesterol groups demonstrated impairment of acetylcholine-mediated endothelium-dependent arterial relaxation compared to chow-fed animals (57 +/- 11% and 45 +/- 9% vs 78 +/- 3%, respectively; P < 0.05). In contrast, vessels from the probucol group demonstrated normal relaxation to acetylcholine (83 +/- 5%). Plasma cholesterol levels and the extent of atherosclerosis were similar among all cholesterol-fed groups. Probucol treatment was associated a threefold increase in LDL resistance to copper-induced oxidative modification (P < 0.05) and a reduction in tissue lipid peroxidation (as assessed by thiobarbituric acid-reactive substances; P < 0.05) compared to animals fed cholesterol alone. Most importantly, both of these changes were strongly correlated with preserved EDRF action. Moreover, cholesterol feeding was associated with a dose-dependent increase in vascular superoxide generation and lysophosphatidylcholine content, both of which were prevented by probucol treatment. From these findings, we conclude that probucol, a lipid-soluble antioxidant, preserves EDRF action in cholesterol-fed rabbits in association with limiting vascular oxidative stress and superoxide generation.Journal of Clinical Investigation 07/1995; 95(6):2520-9. · 12.81 Impact Factor
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ABSTRACT: Restenosis is a frequent long-term complication after balloon angioplasty. Although smooth muscle cells form the major constituent of the occluding lesion, macrophage-derived foam cells are usually also present in high abundance. The latter have the potential to accelerate the rate of reocclusion because they elaborate many potent cytokines and growth factors, which may act to either recruit cells into the neointima or cause neointimal cell proliferation. Macrophage-derived foam-cell formation depends upon the uptake of modified low density lipoprotein via a scavenger receptor-mediated pathway. Foam-cell formation is accompanied by the release of smooth muscle cell mitogens and chemoattractants. We have examined the effects of probucol, a lipid-soluble antioxidant, in the balloon-catheterized carotid artery of the cholesterol-fed rabbit to evaluate the importance of oxidative processes in restenosis. After 5 weeks, serum cholesterol levels were 32% lower (P < 0.05) in rabbits fed 1% probucol with 2% cholesterol, compared with those receiving cholesterol alone. Probucol inhibited neointimal macrophage accumulation by 68% (P < 0.001), reduced absolute intimal size by 51% (P < 0.05), and reduced the intima/media thickness ratio by 51%. These inhibitory effects were directly related to serum probucol concentrations and appeared to be unrelated to probucol's hypocholesterolemic activity. These data suggest that reactive oxygen species may be involved in the intimal response to injury and that antioxidants, such as probucol, may be therapeutically useful as inhibitors of restenosis.Proceedings of the National Academy of Sciences 12/1992; 89(23):11312-6. · 9.74 Impact Factor