Oxidation of low-density lipoprotein

Kim, H.S. and Lee, B.M., Protective effects of antioxidant supplementation on plasma lipid peroxidation in smokers, J. Toxicol. Environ. Health A, 63, 583, 2001. Gaziano, J.M. et al.. Supplementation with beta-carotene in vivo and in vitro does not inhibit low density lipoprotein oxidation. Atherosclerosis, 112, 187, 1995. Sutherland, W.H.F. et al.. Supplementation with tomato juice increases plasma lycopene but does not alter susceptibility to oxidation of low-density lipoproteins from renal transplant recipients, Clin. Nephrol, 52, 30, 1999. 

Jurgens, G., Ashy, A. and Esterbauer, H. (1990). Detection of new epitopes formed upon oxidation of low density lipoprotein, lipoprotein (a) and very low density lipoprotein. Biochem. J. 265, 605-608. 

O Leary, V.J., Darley-Usmar, V.M., Russell, L.J. and Stone, D. (1992). Pro-oxidant efiects of lipoxygenase derived peroxides on the copper initiated oxidation of low density lipoprotein. Biochem. J. 282, 631-634. 

Thomas, C.E. and Jackson, R.L. (1991). Lipid hydroperoxide involvement in copper dependent and independent oxidation of low density lipoproteins. J. Pharmacol. Exp. Ther. 256, 1182-1188. 

Parthasarathy, S., Putz, D.J., Boyd, D., Joy, L. and Steinberg, D. (1986). Macrophage oxidation of low density lipoprotein generates a modified form recognised by the scavenger receptor. Arteriosclerosis 6, 505-510. 

Esterbauer, H., Rotheneder-Dieber, M., Striegl, G. and Waeg, G. (1991). Role of vitamin E in preventing the oxidation of low density lipoprotein. Am. J. Clin. Nutr. 53, 314S-321S. 

Free-radical-induced oxidation of low-density lipoprotein (LDL) may be another mechanism that leads to tissue injury. Following incubation with endothelial or smooth muscle cells, LDL oxidizes and becomes toxic to proliferating fibroblasts (Morel et al., 1983a). 

Gebicki, J.M., Jurgens, G. and Esterbauer, H. (1991). Oxidation of low-density lipoprotein in vitro. In Oxidative Stress, Oxidants and Antioxidants (ed. H. Sies) pp. 371-397. Academic Press, London. 

Hiramatsu, K., Rosen, H., Heinecke, J.W., Wolfbaur, G. and Chait, A. (1987). Superoxide initiates oxidation of low density lipoprotein by human monocytes. Arteriosclerosis 7, 55-60. 

Probucol, another di-r-butyl phenol, is an anti-atherosclerotic agent that can suppress the oxidation of low-density lipoprotein (LDL) in addition to lowering cholesterol levels. The antioxidant activity of probucol was measured, using EPR, with oxidation of methyl linoleate that was encapsulated in liposomal membranes or dissolved in hexane. Probucol suppressed ffee-radical-mediated oxidation. Its antioxidant activity was 17-fold less than that of tocopherol. This difference was less in liposomes than in hexane solution. Probucol suppressed the oxidation of LDL as efficiently as tocopherol. This work implies that physical factors as well as chemical reactivity are important in determining overall lipid peroxidation inhibition activity (Gotoh et al., 1992). 

Esterbauer H, Striegl G, Puhl H, Oberreither S, Rotheneder M, El-Saadani M and Jurgens G. 1989. The role of vitamin E and carotenoids in preventing oxidation of low density lipoproteins. Ann N Y Acad Sci 570 254-267. 

Besides the oxidation of unsaturated acids such as arachidonic and linoleic acids, LOXs are able to oxidize other substrates. One of the most important oxidative processes catalyzed by LOXs is the oxidation of low-density lipoproteins (LDL). (Nonenzymatic LDL oxidation has been discussed in detail in Chapter 25.) As already mentioned, the oxidation of LDL in the arterial intimal space is an important step in the development of atherogenesis. Now, we will consider the involvement of LOXs in this process. In 1989, Parthasarathy et al. [25] found that... 

Y Kuroda, B Cao, A Shibukawa, T Nakagawa. Effect of oxidation of low-density lipoprotein on drug binding affinity studied by high-performance frontal analysis—capillary electrophoresis. Electrophoresis 22 3401—3407, 2001. 

The role of the antioxidant properties of vitamins C, E, and p-carotene in the prevention of cardiovascular disease has been the focus of several recent studies. Antioxidants reduce the oxidation of low-density lipoproteins, which may play a role in the prevention of atherosclerosis. However, an inverse relationship between the intake or plasma levels of these vitamins and the incidence of coronary heart disease has been found in only a few epidemiological studies. One study showed that antioxidants lowered the level of high-density lipoprotein 2 and interfered with the effects of lipid-altering therapies given at the same time. While many groups recommend a varied diet rich in fruits and vegetables for the prevention of coronary artery disease, empirical data do not exist to recommend antioxidant supplementation for the prevention of coronary disease. 

NO also reduces endothelial adhesion of monocytes and leukocytes, key features of the early development of atheromatous plaques. This effect is due to the inhibitory effect of NO on the expression of adhesion molecules on the endothelial surface. In addition, NO may act as an antioxidant, blocking the oxidation of low-density lipoproteins and thus preventing or reducing the formation of foam cells in the vascular wall. Plaque formation is also affected by NO-dependent reduction in endothelial cell permeability to lipoproteins. The importance of eNOS in cardiovascular disease is supported by experiments showing increased atherosclerosis in animals deficient in eNOS by pharmacologic inhibition. Atherosclerosis risk factors, such as smoking, hyperlipidemia, diabetes, and hypertension, are associated with decreased endothelial NO production, and thus enhance atherogenesis. 

Coronary Heart Disease. A theory for atherogenesis (120) has been developed whereby oxidation of low density lipoprotein (LDL) within the arterial wall is the critical first step. It has been hypothesized that sufficient intake of antioxidants would prevent oxidation of LDL and reduce development of coronary heart disease (122). Interest in determining the role of antioxidants in blocking LDL oxidation has led to the development of in vitro test systems. 

Research on carotenoids and cardiovascular disease (CVD) stems from the discovery that the etiology of this disease involves oxidative processes that may be slowed by exogenous antioxidants. One of the best understood processes contributing to development of CVD is the oxidation of low-density lipoprotein (LDL). When LDL becomes oxidized, it is readily taken up by foam cells in the vascular endothelium where it contributes to the development of atherosclerotic lesion. Enhancement of the oxidative stability of LDL may also prevent other oxidative steps involved in clinical expression of coronary disease (e.g., myocardial infarction) and possibly steps not related to LDL oxidation. There is optimism about the potential role of P-carotene in prevention of CVD... 

Dugas, T.R., Morel, D.W., and Harrison, E.H. 1999. Dietary supplementation with b-carotene, but not with lycopene inhibits endothelial cell-mediated oxidation of low-density lipoprotein. Free... 

Rosenblat, M. et al., Macrophage enrichment with the isoflavan glabridin inhibits NADPH oxidase-induced cell-mediated oxidation of low density lipoprotein A possible role for protein kinase C, J. Biol. Chem., 274, 13790, 1999. 

Heinecke JW, et al. Oxidation of low density lipoprotein by thiols superoxide-dependent and -independent mechanisms. J Lipid Res 1993 34(12) 2051 -2061. 

Among polyphenols, resveratrol and its derivatives are thought to play a special role. Resveratrol occurs naturally in grapes in both cis-and trans-isomers, and in their respective glucosides (cis- and trans-piceids). All forms inhibit the oxidation of low density lipoprotein (LDL) and additional benefits. Resveratrol occurs in most red wines but is undetectable or occurs in negligible amounts in dry white wines (Pour Nikfardjam, 2002). 

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