Atherogenicity, oxidation products

As the knowledge of the pathogenesis of atherosclerosis rapidly increases, it appears that an active vascular endothelium, smooth muscle cells, and blood-borne cells such as monocytes and macrophages all play active roles in the atherosclerotic disease process. Risk factors, such as elevated plasma levels of certain lipids, prooxidants, and cytokines, may contribute to the chronic activation/stimulation as well as to the damage of the endothelium and other vascular tissues (160). There is evidence that supports the hypothesis that it is not only pure cholesterol and saturated fats but rather oxidation products of cholesterol and unsaturated fats (and possibly certain pure unsaturated fats) that are atherogenic, possibly by causing endothelial cell injury/dysfiinction. Lipid-mediated endothelial cell dysfunction may lead to adhesion of monocytes, increased permeability of the endothelium to macromolecules, i.e., a decrease in endothelial barrier function, and disturbances in growth control of the vessel wall. 

Even less well understood than MA is the possible occurrence of cholesterol oxidation products in foods and their health significance. It seems clear that some of the products of cholesterol autoxidation are atherogenic. Much more research will be required to establish or refute their proposed carcinogenic properties. Methods for the determination of cholesterol oxidation products in foods and studies to establish levels of occurrence, if any, are most urgently needed. Further studies on antioxidants and procedures for the inhibition of oxidation are also needed. It is difficult to overstate the potential importance to the animal products industry of studies on quantification of cholesterol oxides in food products. Concern about this area of research is becoming widespread (47,48). 

The oxidation hypothesis that oxidatively modified LDL particles are retained in the intima of arteries leading to atherosclerosis is supported by considerable evidence, but remains unproven. The inflammation hypothesis has recently been emphasized in the mediation of all stages of atherosclerosis including initiation, and acute thrombotic complications of atheroma. Since many lipid oxidation products are pro-inflammatory, the inflammation and oxidation hypotheses are closely linked. Oxidized LDL and the oxidized phosphatidylcholine components of LDL are in fact pro-inflammatory and have proatherogenic properties. In addition to LDL, other lipoprotein particles including VLDL and a subfraction called beta VLDL and IDL may undergo oxidation, activate inflammation and become atherogenic. 

Chemical analyses of specific oxidation products can be complemented by quantitative measures of biological changes that create an atherogenic LDL particle, such as increase macrophage intake, electrophoretic mobihty, monocyte binding, or activation of platelets and human leucocytes. Also, many of the... 

Cholesterol oxidation may occur as a result of processing of animal-based food products (Sander et al., 1989 Pie et aL, 1991). This is an undesirable occurrence as cholesterol oxides have been shown to be atherogenic (Pearson et aL, 1983). Recent research has revealed that vitamin E supplementation of food-producing animals, resulted in decreased formation of cholesterol oxidation products in whole-egg powder (Faulkner et al., 1992) and pork products (Monahan et aL, 1992a). 

Retsky, K. L., Freeman, M. W., and Frei, B., 1993, Ascorbic acid oxidation product(s) protect human low density lipoprotein against atherogenic modification, J. Biol. Chem. 268 1304-1309. 

Hubbard, R.W., Ono, Y. and Sanchez, A. (1989) Atherogenic effects of oxidized products of cholesterol. Prog. Food Nutr. Sci. 13, 17-44. 

Although atherosclerosis and rheumatoid arthritis (RA) are distinct disease states, both disorders are chronic inflammatory conditions and may have common mechanisms of disease perpetuation. At sites of inflammation, such as the arterial intima undergoing atherogen-esis or the rheumatoid joint, oxygen radicals, in the presence of transition-metal ions, may initiate the peroxidation of low-density lipoprotein (LDL) to produce oxidatively modified LDL (ox-LDL). Ox-LDL has several pro-inflammatory properties and may contribute to the formation of arterial lesions (Steinberg et /., 1989). Increased levels of lipid peroxidation products have been detected in inflammatory synovial fluid (Rowley et /., 1984 Winyard et al., 1987a Merry et al., 1991 Selley et al., 1992 detailed below), but the potential pro-inflammatory role of ox-LDL in the rheumatoid joint has not been considered. We hypothesize that the oxidation of LDL within the inflamed rheumatoid joint plays a pro-inflammatory role just as ox-LDL has the identical capacity within the arterial intima in atherosclerosis. 

The health impairing and toxic elfects of oxidation of lipids are due to loss of vitamins, polyenoic fatty acids, and other nutritionally essential components formation of radicals, hydroperoxides, aldehydes, epoxides, dimers, and polymers and participation of the secondary products in initiation of oxidation of proteins and in the Maillard reaction. Dilferent oxysterols have been shown in vitro and in vivo to have atherogenic, mutagenic, carcinogenic, angiotoxic, and cytotoxic properties, as well as the ability to inhibit cholesterol synthesis (Tai et ah, 1999 Wpsowicz, 2002). 

V.Z.Lankin, A.M.Vikhert, A.K.Tikhaze, A.S.Nekrasov and S.M.Sogoian, Atherogenic products of cholesterol oxidation, Dokl.Akad.Nauk SSSR 296 (1987) 478-482 (English translation in Doklady Biochemistry). 

The major bioactive products of fatty acid metabolism relevant to atherosclerosis are those that result from enzymatic or non-enzymatic oxidation of polyunsaturated long-chain fatty acids. In most cases, these fatty acids are derived from phospholipase A2-mediated hydrolysis of phospholipids (Chapter 11) in cellular membranes or lipoproteins, or from lysosomal hydrolysis of lipoproteins after internalization by lesional cells. In particular, arachidonic acid is released from cellular membrane phospholipids by arachidonic acid-selective cytosolic phospholipase Aj. In addition, there is evidence that group II secretory phospholipase Aj (Chapter 11) hydrolyzes extracellular lesional lipoproteins, and lysosomal phospholipases and cholesterol esterase release fatty acids from the phospholipids and CE of internalized lipoproteins. Indeed, Goldstein and Brown surmised that at least one aspect of the atherogenicity of LDL may lie in its ability to deliver unsaturated fatty acids, in the form of phospholipids and CE, to lesions (J.L. Goldstein and M.S. Brown, 2001). 

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