Oxidation of human LDL cholesterol

It has now been recognized that oxidation of human LDL cholesterol by free radicals arising from lipid oxidation products maybe involved in the pathogenesis of atherosclerosis, and transition metal... 

There has been an increased interest in natural antioxidants from plant-derived foods and then-by-products for their role in preventing oxidation of human LDL cholesterol. Table 13.8 shows the inhibition of copper-induced human LDL oxidation by hazelnut extracts. Hazelnut skin and hazelnut green leafy cover extracts at 50 ppm concentration effectively inhibited copper-induced oxidation of... 

Retention of P-Carotene and Inhibition of Oxidation of Human LDL Cholesterol... 

As mentioned earlier, oxidation of LDL is initiated by free radical attack at the diallylic positions of unsaturated fatty acids. For example, copper- or endothelial cell-initiated LDL oxidation resulted in a large formation of monohydroxy derivatives of linoleic and arachi-donic acids at the early stage of the reaction [175], During the reaction, the amount of these products is diminished, and monohydroxy derivatives of oleic acid appeared. Thus, monohydroxy derivatives of unsaturated acids are the major products of the oxidation of human LDL. Breuer et al. [176] measured cholesterol oxidation products (oxysterols) formed during copper- or soybean lipoxygenase-initiated LDL oxidation. They identified chlolcst-5-cnc-3(3, 4a-diol, cholest-5-ene-3(3, 4(3-diol, and cholestane-3 3, 5a, 6a-triol, which are present in human atherosclerotic plaques. 

Dr. Joe Vinson of the University of Scranton believes that there is something to the chocolate effect, and he came to Belmont to tell us about his intriguing research. Vinson has determined the total polyphenol content of various chocolates and has also found a way of measuring how effective these mixtures are in preventing the oxidation of human ldl in a test tube. In other words, he has calculated a phenol antioxidant index, which takes into account both the quantity and the quality of these desirable substances. At the symposium Vinson reported that cocoa powder and dark chocolate are the best, followed by milk chocolate. Instant cocoa mixes trail the field. Then Vinson delivered the kicker chocolate has more, and better, polyphenols than fruits or vegetables and more than red wine. A forty-gram bar of dark chocolate has as many polyphenols as a cup of that widely promoted antioxidant cocktail we call tea. But there is still the matter of chocolate s fat content. Researchers tell us, though, that at least half of it is stearic acid, which does not raise blood cholesterol. 

The antiatherosclerotic effect of proanthocyanidin-rich grape seed extracts was examined in cholesterol-fed rabbits. The proanthocyanidin-rich extracts [0.1% and 1% in diets (w/w)] did not change the serum lipid profile, but reduced the level of the cholesteryl ester hydroperoxides (ChE-OOH) induced by 2,2/-azo-bis(2-amidinopropane-dihydrochloride (AAPH), the aortic malonaldehyde (MDA) content and severe atherosclerosis. The immuno-histochemical analysis revealed a decrease in the number of the oxidized LDL-positive macrophage-derived foam cells on the atherosclerotic lesions of the aorta in the rabbits fed the proanthocyanidin-rich extract. When the proanthocyanidin-rich extract was administered orally to the rats, proantho-cyanidin was detected in the plasma. In an in vitro experiment using human plasma, the addition of the proanthocyanidin-rich extract to the plasma inhibited the oxidation of cholesteryl linoleate in the LDL, but not in the LDL isolated after the plasma and the extract were incubated in advance. From these results, proanthocyanidins of the major polyphenols in red wine might trap ROSs in the plasma and interstitial fluid of the arterial wall, and consequently display antiatherosclerotic activity by inhibiting the oxidation of the LDL [92]. 

Dietary MUFA have been found to have several positive effects that include, in addition to lowering human LDL-cholesterol plasma levels, positive effects on lipoprotein oxidation, coagulation, and fibrinolysis (29). Low-fat, monounsaturate-rich diets reduce the susceptibility of low-density lipoproteins to peroxidation ex vivo (30). In hypercholesterolemic subjects, diets containing MUFA resulted in favorable alterations in the fatty acid composition and oxidative profile of LDL in hypercholesterolemic subjects that were characterized as an increase in lipid peroxide lag time and a decrease in lipid peroxide formation (30). In animal studies. 

Probucol. Probucol is an antioxidant that is effective in lowering LDL cholesterol. Whereas probucol was known to lower cholesterol after relatively simple clinical trials (160), its mechanism of action as an antioxidant in the treatment of atherosclerosis is quite novel. Probucol has been shown to have the abiUty to produce regression of atherosclerotic lesions in animal models (161). Probucol therefore represents a novel class of pharmaceutical agent for the treatment of atherosclerosis. This effect occurs mechanistically, in part, by preventing oxidation of LDL, a necessary step in foam cell formation. This antioxidant activity has been shown in laboratory experiments and its activity in lowering LDL cholesterol in human studies is well documented (162). 

Although significance of cholesterol hydroperoxides formation under physiological conditions is still unknown, they are apparently very important factors in the development of many pathophysiological disorders. Thus it has been shown [87] that 13ZE-Chl8 2-OOH exists in vivo in atherosclerotic lesions and is the primary toxin of oxidized human LDL. 

Belkner et al. [32] demonstrated that 15-LOX oxidized preferably LDL cholesterol esters. Even in the presence of free linoleic acid, cholesteryl linoleate continued to be a major LOX substrate. It was also found that the depletion of LDL from a-tocopherol has not prevented the LDL oxidation. This is of a special interest in connection with the role of a-tocopherol in LDL oxidation. As the majority of cholesteryl esters is normally buried in the core of a lipoprotein particle and cannot be directly oxidized by LOX, it has been suggested that LDL oxidation might be initiated by a-tocopheryl radical formed during the oxidation of a-tocopherol [33,34]. Correspondingly, it was concluded that the oxidation of LDL by soybean and recombinant human 15-LOXs may occur by two pathways (a) LDL-free fatty acids are oxidized enzymatically with the formation of a-tocopheryl radical, and (b) the a-tocopheryl-mediated oxidation of cholesteryl esters occurs via a nonenzymatic way. Pro and con proofs related to the prooxidant role of a-tocopherol were considered in Chapter 25 in connection with the study of nonenzymatic lipid oxidation and in Chapter 29 dedicated to antioxidants. It should be stressed that comparison of the possible effects of a-tocopherol and nitric oxide on LDL oxidation does not support importance of a-tocopherol prooxidant activity. It should be mentioned that the above data describing the activity of cholesteryl esters in LDL oxidation are in contradiction with some earlier results. Thus in 1988, Sparrow et al. [35] suggested that the 15-LOX-catalyzed oxidation of LDL is accelerated in the presence of phospholipase A2, i.e., the hydrolysis of cholesterol esters is an important step in LDL oxidation. 

The expression of 15-LOX in atherosclerotic lesions is one of the major causes of LDL oxidative modification during atherosclerosis. To obtain the experimental evidence of a principal role of 15-LOX in atherosclerosis under in vivo conditions, Kuhn et al. [67] studied the structure of oxidized LDL isolated from the aorta of rabbits fed with a cholesterol-rich diet. It was found that specific LOX products were present in early atherosclerotic lesions. On the later stages of atherosclerosis the content of these products diminished while the amount of products originating from nonenzymatic lipid peroxidation increased. It was concluded that arachidonate 15-LOX is of pathophysiological importance at the early stages of atherosclerosis. Folcik et al. [68] demonstrated that 15-LOX contributed to the oxidation of LDL in human atherosclerotic plaques because they observed an increase in the stereospecificity of oxidation in oxidized products. Arachidonate 15-LOX is apparently more active in young human lesions and therefore, may be of pathophysiological importance for earlier atherosclerosis. In advanced human plaques nonenzymatic lipid peroxidation products prevailed [69],... 

Hypolipemic activity. Fiber, administered orally to nine adults with ileostomies at a dose of 13 g/day, increased the excretion of cholesterol " Petroleum ether extract of the fresh fruit, administered to pigs at a concentration of 3.5 g/kg of diet, was inactive "" . Purified green barley extract, in human mononuclear culture of cells isolated from perithelial blood and synovial fluid of patients with rheumatoid arthritis, was active . Leaf essence, administered to atherosclerotic New Zealand White male rabbits at a dose of 1% of diet, produced a decrease of plasma total cholesterol, triacylglycerol, lucigenin-chemilumines-cence, and luminal-chemiluminescence levels. The value of Tj of red blood cell hemolysis and the lag phase of LDL oxidation increased in barley-treated group compared with the control. Ninety percent of the intimal surface of the thoracic aorta was covered with atherosclerotic lesions in the... 

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