There are a substantial number of large epidemiological studies examining the relationship between dietary ATC intake and cardiovascular disease mortality (reviewed in [116-118]). For example, studies carried out two decades ago showed a correlation between higher than expected mortality and very low dietary ATC intakes (as well as with very high ATC intakes ). The basis of its cardioprotective effects is the ability of ATC to reduce damage caused by ROS in general, and specifically to inhibit the oxidation and MDA-modification of unsaturated lipids in low-density lipoprotein (LDL) particles [116,120,121], These oxidized products ofLDL are highly damaging and initiate the formation of atherosclerotic plaques and lesions and are related to the course of myocardial infarction [116,122]. However, atherosclerotic plaque formation and the mechanisms for the ensuing increased morbidity and mortality are complex processes, which involve, for example, the production of superoxide by monocytes, and the formation of autoantibodies against oxidized LDL and MDA-LDL [123,124], In aortic muscle or endothelial cells in vitro, oxidized LDL can increase collagen and fibronectin synthesis, apoptosis, intracellular calcium and TBA formation [122,125], Moreover, concomitant pathologies such as hypertension are additional risk factors for the etiology of atherosclerosis. For example, in hypertension, ATC status as reflected by red blood cell (but not plasma), concentrations is lower than that of normotensive controls , Age-related reductions in the anti-oxidant capacity of plasma, acting against peroxyl radicals, may also contribute to the atherosclerosis , There is also a tentative association between dietary ATC intake and increased (deemed to be cardioprotective) serum HDL-cholesterol [1281,
Apoptosis induced in smooth muscle cells in vitro by oxidized-LDL can be prevented with anti-oxidants , ATC and Trolox (a water-soluble form of ATC), but not alpha-tocopheryl acetate or alpha-tocopheryl succinate can ameliorate these adverse changes in the levels of TBARS and intracellular calcium , More recently, the novel synthetic ATC-analogue IRFI005 (i.e., a metabolite ofIRFI0016) has been shown to prevent the oxidation of LDL ,
Monocytes are involved in the formation of atherosclerotic plaque and lesions via their ability to generate ROS (for example the superoxide radical) and cytokines such as interleukin (IL)-lbeta [123,124], ATC treatment of these cells prevents IL-l-beta formation (a cytokine involved in atherosclerosis), and superoxide and hydrogen peroxide production by monocytes in vitro when stimulated with lipopolysaccharide [123,124], The mechanism of this protective effect appears to be related to the ability of ATC to inhibit protein kinase C activity , Studies have also shown that alpha-tocopherol, but not beta-tocopherol, is able to reduce the activation of protein-kinase C by endothelin and thrombin ,
The potential significance of these in vitro data needs to be discussed in relation to the prevention of atherosclerosis by ATC in vivo, although consideration need to be given to the possibility that other pharmacological preparations may be equally promising in reducing the oxidation ofLDL. Such candidates include analogues of tetronic acid (for example 4-(4'-chloro-l,l'-biphenyl)-2-hydroxytetronic acid), which are able to inhibit hepatic membrane lipid peroxidation and LDL oxidation in vitro to a greater extent than Trolox . Some authors have questioned whether blood levels oflipophilic antioxidants reflect the development of atherosclerosis , In a comparison between patients with coronary heart disease and controls, gamma-tocopherol levels were significantly lower in patients with coronary heart disease, although in contrast no such differences were observed for ATC , In other studies, patients with coronary artery disease (for example, angina or myocardial infarction) were shown to have lower serum ATC compared to healthy controls [133,134], It is nevertheless important to consider that the defense against ROS is represented by a number of antioxidants. Thus, alpha- and beta-carotene levels are reduced in subjects with coronary heart disease, although levels of ubiquinol-10 are not , In another study of 4,802 subjects aged between 55-95 years, the risk of myocardial infarction was higher in the low intake beta-carotene group although no association of myocardial infarction with ATC (and vitamin C) intake was observed , In an earlier study, antioxidant levels were examined in a cohort of patients with coronary heart disease, which were subgrouped into those with stable and unstable angina pectoris , Overall, these subjects had higher levels of cholesterol, LDL-cholesterol and lipoprotein(a) and lower HDL-cholesterol , However, total plasma ATC was comparable in all three groups (control, stable angina and unstable angina), except when expressed per LDL particle, whereupon it was lower in patents with unstable angina pectoris. Values in patents with stable angina pectoris were higher than the latter, but lower than controls , Thus, it seems that the type of cardiovascular disorder needs to be defined and careful attention needs to be paid as to how ATC levels are expressed. Internal factors relevant to the determination of ATC status include triglycerides and apoproteins , However, geographical and cultural dietary habits further compound the relationship between ATC and the etiology ofheart disease. Whole grain intake and nuts correlate negatively with coronary heart disease, which is not explained by the contribution of ATC (nor fiber, folate, vitamin B6) [137,138], Another example pertains to phenolic compounds which occur in wine and appear to be able to increase plasma ATC levels and inhibit platelet aggregation [139,140], Resveratrol, quercetin and other phenolic compounds, which are often found in alcoholic beverages (particularly red wine) and other foodstuffs are claimed to have antioxidant properties (which may be greater than ATC). This may contribute to the French Paradox in which there is a reduced risk of cardiovascular mortality due to moderate alcohol consumption [141-145], However, many of the studies on the role of antioxidants in red wine in reducing LDL oxidation in vivo have been questioned , In a controlled study of 25 subjects given either red or white wine for 4 weeks, susceptibly of LDL to oxidation in vitro was not altered and similar negative effects were obtained for levels of plasma ATC, urate, vitamin C, glutathione and ubiquinol-10 , It is clear that some epidemiological studies show beneficial correlations between ATC intake and risk of cardiovascular disease, and laboratory studies demonstrate positive effects of ATC in vivo and in vitro. These data need to be interpreted in terms of potential therapeutic benefits of ATC supplementation, and its use to reduce overall mortality has been advocated , Clinical studies have shown that oxidized serum lipids in patients with hypercholesterolemia can be ameliorated with ATC , In the CHAOS (Cambridge Heart Antioxidant Study), 2,002 subjects with coronary atherosclerosis (confirmed angiographically) were shown to benefit from ATC supplementation, via a reduction in the incidence of non-fatal myocardial infarction, though an increase in overall mortality (not achieving significance) was reported , In a study ofll,178 subjects aged between 67 and 105, ATC supplementation reduced overall mortality (relative risk: 0.66) and mortality due to coronary disease (relative risk of 0.37) , In the GISSI (Gruppo Italiano per lo Studio della Soprawivenza nell'Infarto miocardico) trial, over 11,000 subjects were recruited and supplemented with either n-3 polyunsaturated fatty acids, ATC, both ATC and n-3 polyunsaturated fatty acids, or none , n-3 polyunsaturated fatty acids were found to be of benefit, in reducing mortality and cardiovascular death , However, ATC conferred no such benefit and the combined n-3 polyunsaturated fatty acid and STC therapy was similar to n-3 polyunsaturated fatty acid alone , Although, some of these large studies were negative in their findings, it is important to re-emphasize that ATC intake alone is not the only nutrient or factor that correlates with reduced incidence of coronary disease. For example, increasing intake of dietary fiber, independent of fat intake, correlates with reduced incidence of cardiovascular disease as does vitamin B6 and folate [151,1521.
High fat or high-cholesterol containing diets are often used in animal studies to promote atherosclerosis, as a model for examining pathogenic mechanisms in the etiology of cardiovascular disease in vivo. Animal studies have shown that ATC supplementation in rabbits fed high cholesterol containing diets results in reduced blood cholesterol levels , A combination of dietary ATC and selenium supplementation is effective in reducing atherosclerotic lipid deposits in myocardial vessels, as well as blood markers of oxidative stress such as MDA [139,154], Smooth muscle cells from aorta of cholesterol-fed rabbits have increased protein kinase C levels, which are not significantly ameliorated by ATC treatment ,
Heart tissue is also impaired in diabetes, leading to contractile dysfunction that may also result from increased cardiac lipid peroxidation and altered fatty acid profiles [98,156],
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