Do free radicals play causal role in atherosclerosis? Low density lipoprotein oxidation and vitamin E revisited

Lipid peroxidation induced by free radicals has been implicated in the pathogenesis of various diseases. Numerous in vitro and animal studies show that oxidative modification of low density lipoprotein (LDL) is an important initial event of atherosclerosis. Vitamin E and other antioxidants inhibit low density lipoprotein oxidation efficiently in vitro, however, human clinical trials with vitamin E have not yielded positive results. The mixed results for vitamin E effect may be ascribed primarily to the two factors. Firstly low density lipoprotein oxidation proceeds by multiple pathways mediated not only by free radicals but also by other non-radical oxidants and vitamin E is effective only against free radical mediated oxidation. Secondly, in contrast to animal experiments, vitamin E is given at the latter stage where oxidation is no more important. Free radicals must play causal role in pathogenesis of atherosclerosis and vitamin E should be effective if given at right time to right subjects.     

Antioxidants protect from atherosclerosis by a heme oxygenase-1 pathway that is independent of free radical scavenging

Oxidative stress is implicated in atherogenesis, yet most clinical trials with antioxidants, particularly vitamin E, have failed to protect against atherosclerotic diseases. A striking exception is probucol, which retards atherosclerosis in carotid arteries and restenosis of coronary arteries after angioplasty. Because probucol has in vitro cellular-protective effects independent of inhibiting lipid oxidation, we investigated the mode of action of probucol in vivo. We used three models of vascular disease: apolipoprotein E-deficient mice, a model of atherosclerosis; rabbit aortic balloon injury, a model of restenosis; and carotid injury in obese Zucker rats, a model of type 2 diabetes. Unexpectedly, we observed that the phenol moieties of probucol were insufficient, whereas its sulphur atoms were required for protection. Probucol and its sulphur-containing metabolite, but not a sulphur-free phenolic analogue, protected via cell-specific effects on inhibiting macrophage accumulation, stimulating reendothelialization, and inhibiting vascular smooth muscle cell proliferation. These processes were mediated via induction of heme oxygenase-1 (HO-1), an activity not shared by vitamin E. Our findings identify HO-1 as the molecular target of probucol. They indicate 2-electron rather than radical (1-electron) oxidants as important contributors to atherogenesis, and point to novel lead compounds for therapeutic intervention against atherosclerotic diseases.     

Vitamin E supplementation in the prevention of coronary heart disease.

Vitamin E consists of a number of compounds, tocopherols and tocotrienols, that function as lipid-soluble antioxidants. A hypothesis is that vitamin E may slow the progression of atherosclerosis by blocking the oxidative modification of low-density lipoprotein cholesterol and thus decrease its uptake into the arterial lumen. Basic science and animal studies have generally supported this hypothesis. Observational studies have primarily assessed patients with no established coronary heart disease (CHD), and results have generally supported a protective role of vitamin E in CHD. Early primary and secondary prevention clinical trials (Alpha-Tocopherol, Beta-Carotene Cancer Protection study and Cambridge Heart Antioxidant Study) showed mixed results. Despite years of encouraging evidence from basic science and observational studies, 3 large randomized clinical trials (Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto miocardico, Heart Outcomes Prevention Evaluation, and Primary Prevention Project) with a combined total of more than 25,000 patients failed to show a significant benefit with vitamin E taken as a dietary supplement for the prevention of CHD. Four large randomized primary prevention trials currently under way should add to our knowledge. The American Heart Association has recommended consumption of a balanced diet with emphasis on antioxidant-rich fruits and vegetables but has made no recommendations regarding vitamin E supplementation for the general population. Although vitamin E supplementation seems to be safe for most people, recommendations from health care professionals should reflect the uncertainty of established benefit as demonstrated in clinical trials.     

Role of vitamin E in the prophylaxis of cancer

Vitamin E may have anticancer properties as a lipid antioxidant and free radical scavenger. Some animal studies support this hypothesis, although findings are contradictory. Most human studies on the role of vitamin E in cancer etiology have been of case-control or cohort design. The results of such studies on whether vitamin E intake reduces the risk of cancer do not generally support the hypothesis of its protective effect, possibly owing to methodological issues. Some of the case-control studies, however, have shown lower concentrations of vitamin E in the serum of patients with cancer than in the controls. Cohort studies also generally show a low level of serum vitamin E associated with a slightly increased risk of cancer, though the strength of this association varies between populations and subgroups, as well as for different cancer sites. No definite conclusions about a causal connection between vitamin E and the occurrence of cancer can be drawn until the final results of current large-scale intervention trials are published.     

Enterolactone as a risk factor for breast cancer: a review of the published evidence

Lignans are natural plant compounds with estrogenic properties and are probably the most important source of phytoestrogens in western diets. They have been suggested to have anticarcinogenic potential. For an evaluation of the effect of these compounds, namely enterolactone, on breast cancer risk, we have reviewed the literature available on major epidemiological studies. We analyzed methodological issues, the design and results of 3 studies providing data on enterolactone dietary intake, 3 studies on urinary excretion and 4 studies concerning blood measurements of enterolactone. All studies on dietary intake were retrospective and based on questionnaires. Two studies showed a significant inverse relationship between dietary lignans consumption and breast cancer incidence, specifically in premenopausal women. No effect was evident in the third study. Among the urinary enterolactone excretion studies, two studies (one retrospective, the other prospective) showed a definite protective effect. However, one retrospective study failed to show any significant interaction. Again, conflicting results were obtained from enterolactone blood measurement studies: two studies demonstrated a protective effect due to enterolactone in premenopausal women, while the other two studies failed to demonstrate any association. In summary, epidemiological evidence to date is conflicting. Prospective large scale studies will require assessing the consumption of antibiotics and dietary habits during adolescence in order to obtain definitive conclusions.     

Beta-carotene inhibits atherosclerosis in hypercholesterolemic rabbits.

Oxidatively damaged LDL may be of central importance in atherogenesis. Epidemiological evidence suggests that high dietary intakes of beta-carotene and vitamin E decreases the risk for atherosclerotic vascular disease, raising the possibility that lipid-soluble antioxidants slow vascular disease by protecting LDL from oxidation. To test this hypothesis, we fed male New Zealand White rabbits a high-cholesterol diet or the same diet supplemented with either 1% probucol, 0.01% vitamin E, 0.01% all-trans beta-carotene, or 0.01% 9-cis beta-carotene; then we assessed both the susceptibility of LDL to oxidation ex vivo and the extent of aortic atherosclerosis. As in earlier studies, probucol protected LDL from oxidation and inhibited lesion formation. In contrast, vitamin E modestly inhibited LDL oxidation but did not prevent atherosclerosis. While beta-carotene had no effect on LDL oxidation ex vivo, the all-trans isomer inhibited lesion formation to the same degree as probucol. Moreover, all-trans beta-carotene was undetectable in LDL isolated from rabbits fed the compound, although tissue levels of retinyl palmitate were increased. The effect of all-trans beta-carotene on atherogenesis can thus be separated from the resistance of LDL to oxidation, indicating that other mechanisms may account for the ability of this compound to prevent vascular disease. Our results suggest that metabolites derived from all-trans beta-carotene inhibit atherosclerosis in hypercholesterolemic rabbits, possibly via stereospecific interactions with retinoic acid receptors in the artery wall.     

Update on vitamin supplements for the prevention of coronary disease and stroke

Dietary antioxidants and folic acid may play a role in the pathophysiology of coronary disease and stroke. We review patient-oriented evidence on the effectiveness of supplementation with antioxidants and/or folic acid in the prevention of myocardial infarction and stroke. Observational data suggest cardiovascular benefit of vitamin E supplementation, but results of controlled clinical trials are inconsistent regarding the effect on nonfatal myocardial infarction. Moreover, studies have not shown a protective effect of vitamin E against fatal myocardial infarction and have not addressed stroke. For vitamin C and folic acid supplementation, observational data are inconsistent and controlled clinical trials are lacking. Thus, the available evidence is insufficient to recommend the routine use of vitamin E, vitamin C or folate supplements for the prevention of myocardial infarction or stroke. The evidence argues against the use of beta carotene supplements for this purpose. The costs and risks associated with these supplements are low, however, and physicians may choose to recommend vitamin E, folate and/or vitamin C supplementation pending conclusive evidence from clinical trials.     

The use of antioxidants in retarding atherosclerosis: fact or fiction?

The proposal that antioxidants may retard the progression of atherosclerosis is not new. Published studies examining the effect of antioxidants on experimental antioxidants extend back to 1940. The results have all been inconsistent. However, the data regarding the beneficial effects of retarding atherosclerotic progression are strong enough to warrant continued research on the lipoprotein oxidation theory or atherosclerosis. However, caution is needed to avoid embracing a concept without proof. It should be noted that the National Cholesterol Education Program does not recommend the use of antioxidant vitamin supplements to reduce CAD. Atherogenesis is produced by multiple factors. To believe that all such factors are mediated by uncontrolled oxidative events is, to say the least, naive. Finally, should antioxidants prove to be effective in retarding coronary atherosclerosis, their place on the therapeutic ladder of CAD prevention would be low. The overwhelmingly proven evidence favors the following factors that have been proven to lower morbidity and mortality due to atherosclerosis: (a) treatment of hypertension, (b) cessation of tobacco use, (c) treatment of dyslipidemia, (d) achieving a normal weight, (e) regular exercise, (f) treatment of homocystinuria, especially in cases with renal disease, and (g) antioxidants.     

Coronary heart disease prevention: nutrients, foods, and dietary patterns

Diet is a key modifiable risk factor in the prevention and risk reduction of coronary heart disease (CHD). Results from the Seven Countries Study in the early 1970s spurred an interest in the role of single nutrients such as total fat in CHD risk. With accumulating evidence, we have moved away from a focus on total fat to the importance of considering the quality of fat. Recent meta-analyses of intervention studies confirm the beneficial effects of replacing saturated fat with polyunsaturated fatty acids on CHD risk. Scientific evidence for a detrimental role of trans fat intake from industrial sources on CHD risk has led to important policy changes including listing trans fatty acid content on the "Nutrition Facts" panel and banning the use of trans fatty acids in food service establishments in some cities. The effects of such policy changes on changes in CHD incidence are yet to be evaluated. There has been a surging interest in the protective effects of vitamin D in primary prevention. Yet, its associations with secondary events have been mixed and intervention studies are needed to clarify its role in CHD prevention. Epidemiological and clinical trial evidence surrounding the benefit of B vitamins and antioxidants such as carotenoids, vitamin E, and vitamin C, have been contradictory. While pharmacological supplementation of these vitamins in populations with existing CHD has been ineffective and, in some cases, even detrimental, data repeatedly show that consumption of a healthy dietary pattern has considerable cardioprotective effects for primary prevention. Results from these studies and the general ineffectiveness of nutrient-based interventions have shifted interest to the role of foods in CHD risk reduction. The strongest and most consistent protective associations are seen with fruit and vegetables, fish, and whole grains. Epidemiological and clinical trial data also show risk reduction with moderate alcohol consumption. In the past decade, there has been a paradigm shift in nutritional epidemiology to examine associations between dietary patterns and health. Several epidemiological studies show that people following the Mediterranean style diet or the Dietary Approaches to Stop Hypertension (DASH) diet have lower risk of CHD and lower likelihood of developing hypertension. Studies using empirical or data driven dietary patterns have frequently identified two patterns - "Healthy or Prudent" and "Western". In general, the "Healthy", compared to the "Western" pattern has been associated with more favorable biological profiles, slower progression of atherosclerosis, and reduced incidence. Evidence on changes in dietary patterns and changes in CHD risk is still emerging. With the emergence of the concept of personalized nutrition, studies are increasingly considering the role of genetic factors in the modulation of the association between nutrients and CHD. More studies of genetic variation and dietary patterns in relation to CHD are needed.     

Can anti–oxidants prevent ischaemic heart disease?

Ischaemic heart disease remains a major cause of mortality in developed countries. A number of important risk factors for the development of coronary atherosclerosis have been identified including hypertension, hypercholesterolaemia, insulin resistance and smoking. However, these factors can only partly explain variations in the incidence of ischaemic heart disease either between populations or within populations over time. In addition, population interventions based upon these factors have had little impact in the primary prevention of heart disease. Recent evidence suggests that one of the important mechanisms predisposing to the development of atherosclerosis is oxidation of the cholesterol–rich low–density lipoprotein particle. This modification accelerates its uptake into macrophages, thereby leading to the formation of the cholesterol–laden ‘foam cell’. In vitro, low–density lipoprotein oxidation can be prevented by naturally occurring anti–oxidants such as vitamin C, vitamin E and beta–carotene. This article explores the evidence that these dietary anti–oxidants may influence the rate of progression of coronary atherosclerosis in vivo and discusses the need for formal clinical trials of anti–oxidant therapy.     

Oxidative Stress in COPD and Its Measurement through Exhaled Breath Condensate

Oxidative stress and airway inflammation together form a vicious cycle, which is responsible for the disease progression in chronic pulmonary obstructive disease (COPD). The damaging effects of oxidative stress accumulate over the years, causing increased bronchial hyperresponsiveness and inflammation and destruction of airway epithelial cells and impairing the functions of antiproteases and surfactant. Although the lung expresses a number of antioxidants, cigarette smoking and recurrent infections associated with this disease overwhelm this protective mechanism. Studies of antioxidants in COPD have yielded conflicting results, probably due to the compartmentalization of these mediators, and because of the fact that the lung is a difficult organ to sample. Chronic exposure to oxidants upregulates the production of antioxidants, which become depleted during acute exacerbations. Future studies of the pathogenesis of COPD require a noninvasive yet accurate sampling procedure, of which exhaled breath condensate (EBC) is a good candidate. EBC samples the epithelial lining fluid, which contains the local oxidative stress markers in the lung. Oxidative stress markers such as hydrogen ions, hydrogen peroxide, 8‐isoprostanes, thiobarbituric acid reactive products, nitrosothiols, and nitrite/nitrate have been identified in EBC of COPD patients, whereas many other markers of the oxidative‐antioxidative balance have yet to be investigated.     

Oxidative susceptibility of unfractionated serum or plasma: response to antioxidants in vitro and to antioxidant supplementation

BACKGROUND: The susceptibility of plasma lipids to oxidation is thought to be a factor contributing to atherogenic risk. Various groups have studied the in vitro oxidizability of isolated LDL and examined the effects of conventional antioxidants. The drawbacks associated with the isolation of LDL for evaluation of in vitro oxidizability, however, have limited the application of this measurement in large-scale studies. METHODS: We developed and evaluated an assay that can be used to directly assess the oxidative susceptibility of unfractionated serum or plasma lipids, obviating the need for isolation of lipoprotein fractions. Oxidative conditions were initiated in vitro with cuprous chloride and 2,2'-azobis(2-amidinopropane) hydrochloride. The effects of antioxidants added in vitro, and as an oral supplement, were monitored by conjugated diene formation. RESULTS: The addition of ascorbic acid (0-50 micromol/L) in vitro elicited a dose-dependent protective effect, increasing the lag time to oxidation (P < 0.001). In contrast, alpha-tocopherol demonstrated prooxidant behavior at increasing concentrations (0-50 micromol/L), although we observed a decrease in the maximum rate of oxidation. Our findings are supported by the results from plasma samples of participants in a randomized antioxidant (vitamins C and E) intervention study after acute ischemic stroke. The group receiving vitamins C and E for 14 days showed an increased lag time to plasma lipid oxidation in vitro compared with the nonsupplemented group (P < 0.05). CONCLUSION: The susceptibility of unfractionated plasma or serum lipids to oxidation in vitro offers an alternative to LDL for evaluating the efficacy of antioxidant regimens.     

Alpha-tocopherol: roles in prevention and therapy of human disease.

Alpha-tocopherol, one of the eight isoforms of vitamin E, is the most potent fat-soluble antioxidant known in nature. For years, it was thought that alpha-tocopherol only functioned as a scavenger of lipid peroxyl radicals, specifically, oxidized low-density lipoprotein (oxLDL), thereby serving as a chief antioxidant for the prevention of atherosclerosis. In recent years, the many roles of alpha-tocopherol have been uncovered, and include not only antioxidant functions, but also pro-oxidant, cell signaling and gene regulatory functions. Decades of clinical and preclinical studies have broadened our understanding of the antioxidant vitamin E and its utility in a number of chronic, oxidative stress-induced pathologies. The results of these studies have shown promising, albeit mixed reviews on the efficacy of alpha-tocopherol in the prevention and treatment of heart disease, cancer and Alzheimer's disease. Future studies to uncover cellular and systemic mechanisms may help guide appropriate clinical treatment strategies using vitamin E across a diverse population of aging individuals.     

Vitamin D deficiency and severe asthma

Vitamin D has received tremendous amount of attention recently due to the ever-increasing reports of association between vitamin D deficiency and a wide range of conditions, from cancer to fertility to longevity. The fascination of disease association with vitamin D deficiency comes from the relatively easy solution to overcome such a risk factor, that is, either by increase in sun exposure and/or diet supplementation. Many reviews have been written on a protective role of vitamin D in asthma and related morbidities; here, we will summarize the epidemiological evidence supporting a role of vitamin D against hallmark features of severe asthma, such as airway remodeling and asthma exacerbations. Furthermore, we discuss data from in vitro and in vivo studies which provide insights on the potential mechanisms of how vitamin D may protect against severe asthma pathogenesis and how vitamin D deficiency may lead to the development of severe asthma. Approximately 5–15% of asthmatic individuals suffer from the more severe forms of disease in spite of aggressive therapies and they are more likely to have irreversible airflow obstruction associated with airway remodeling. At present drugs commonly used to control asthma symptoms, such as corticosteroids, do not significantly reverse or reduce remodeling in the airways. Hence, if vitamin D plays a protective role against the development of severe asthma, then the most effective therapy may simply be a healthy dose of sunshine.     

Effect of short-term mechanical stimulation on the salivary concentrations of vitamin C,vitamin E,total antioxidant capacity and total oxidant status

Oxidative stress biomarkers of oral and systemic diseases can be found in saliva. However, there is no uniformity for the saliva collection time in these kinds of analyses and saliva composition may change because of mechanical stimulation. Therefore, the aim of this work was to determine the effect of mechanical stimulation for 10 min on the concentrations of vitamin C, vitamin E, total antioxidants and total oxidants in saliva. Saliva samples from individuals of both sexes, aged between 18 and 38 years, were collected for 10 min at 2 minintervals. Saliva flow rate in each 2 min period was measured, as well the total oxidant state, the total antioxidant capacity, vitamin C and vitamin E concentrations. All analyses were performed in triplicate and were determined using colorimetric tests. The results were analysed using t-test, Friedman’s test and analysis of variance (ANOVA) for repeated measures. Mauchly’s sphericity test was applied and, if necessary, technical corrections were made using the Greenhouse–Geisser test. We found no significant difference between the amounts of saliva produced across the collection times. Total oxidant status, total antioxidant capacity, vitamin C and vitamin E concentrations remained stable. Based on our findings, saliva can be collected for 10 min or less with masticatory stimulation without any variations in the concentration of the variables analysed. However, we suggest using saliva samples after two minutes of mechanical stimulation.     

Risk factors and current chemoprevention studies in prostate cancer

There are no established risk factors for prostate cancer other than age, ethnic group, and family history. For dietary factors, the WCRF/AICR reported that diets high in vegetables were possibly protective, and that regular consumption of red meat, fat, saturated/animal fat, and milk and any products possibly increased risk. Among nutritional factors, a protective effect of lycopene, vitamin E, selenium, and perhaps fish oil and phytoestrogens appear particularly promising, although no definite answers have yet emerged. Although hormonal influences are biologically plausible, observational studies of androgen have not produced consistent results. While, insulin-like growth factor 1 could be a risk factor. Based on these evidences, several chemoprevention trials were launched using 5-alpha reductase inhibitor, selenium, vitamin E and so on.     

Traditional and alternative nutrition--levels of homocysteine and lipid parameters in adults

Values of homocysteine and lipid parameters were measured in groups of adults consuming alternative nutrition (vegetarians/lactoovo/, vegans) and compared with a group consuming traditional diet (omnivores, general population). Frequency of hyperhomocysteinemia was 53% in the vegans group, 28% in vegetarians vs. 5% in omnivores. In conditions of lower methionine intake (reduced content in plant proteins), the remethylation pathway of homocysteine metabolism prevails and it is vitamin B12 and folate-dependent. The intake of vitamin B12 is equal to zero in vegans; vegetarians consume 124% of the RDA vs. 383% in omnivores. Serum vitamin levels are significantly lower in subjects consuming alternative nutrition with deficiency observed in 24% of vegetarians, 78% of vegans vs. 0% in omnivores. Serum folate levels are within the reference range in all groups. Mild hyperhomocysteinemia in the groups consuming alternative diet is a consequence of vitamin B12 deficiency. Vegetarians and vegans meet the RDA for energy and fat, and have a favourable proportion of saturated, mono- and polyunsaturated fatty acids on total energy intake; the ratio of linoleic/alpha-linolenic acid in their diet corresponds with the recommendations. They have low cholesterol consumption and higher vitamin E and C intake. Optimal fat intake of correct composition is reflected in lower values of atherosclerosis risk factors (cholesterol, LDL-cholesterol, atherogenic index, saturated fatty acids, triacylglycerols), and significantly higher levels of protective substances (linoleic acid, alpha-linolenic acid, HDL-cholesterol, vitamin E, vitamin E/cholesterol, vitamin C). Low lipid risk factors but higher findings of mild hyperhomocysteinemia in vegetarians mean a diminished protective effect of alternative nutrition in cardiovascular disease prevention.     

Protective effects of antioxidant micronutrients (vitamin E, zinc and selenium) in type 2 diabetes mellitus.

Type 2 diabetes (T2D) is a major cause of vascular complications affecting heart, kidney, retina and peripheral nerves. Hyperglycaemia leads to oxidative stress that plays an important role in vascular degenerative lesions observed in diabetes. In this Review we consider whether vitamin E, zinc or selenium are involved in the pathogenesis of diabetes. Concerning vitamin E, major epidemiological studies do not give the expected results in preventing cardiovascular outcomes. The mechanisms of free radical overproduction in diabetes could explain these results. Superoxide anion overproduction originates from mitochondria; in these conditions antioxidant enzymes are more relevant to reduce oxygen species than vitamin E. Zinc has numerous targets to modulate insulin activity, including its antioxidant capacity. Zinc status is decreased in most T2D patients. The effect of zinc supplementation on antioxidant status is raised when complications are associated. Selenium is a major antioxidant trace element and is the co-factor of glutathione peroxidase (Se GSHpx). Low Se GSHpx activity, observed in diabetic patients, is associated with thrombosis and cardiovascular complications.     

Inflammation in the vascular bed: importance of vitamin C

Despite decreases in atherosclerotic coronary vascular disease over the last several decades, atherosclerosis remains a major cause of mortality in developed nations. One possible contributor to this residual risk is oxidant stress, which is generated by the inflammatory response of atherosclerosis. Although there is a wealth of in vitro, cellular, and animal data supporting a protective role for antioxidant vitamins and nutrients in the atherosclerotic process, the best clinical trials have been negative. This may be due to the fact that antioxidant therapies are applied "too little and too late." This review considers the role of vitamin C, or ascorbic acid in preventing the earliest inflammatory changes in atherosclerosis. It focuses on the three major vascular cell types involved in atherosclerosis: endothelial cells, vascular smooth muscle cells, and macrophages. Ascorbate chemistry, recycling, and function are described for these cell types, with emphasis on whether and how the vitamin might affect the inflammatory process. For endothelial cells, ascorbate helps to prevent endothelial dysfunction, stimulates type IV collagen synthesis, and enhances cell proliferation. For vascular smooth muscle cells, ascorbate inhibits dedifferentiation, recruitment, and proliferation in areas of vascular damage. For macrophages, ascorbate decreases oxidant stress related to their activation, decreases uptake and degradation of oxidized LDL in some studies, and enhances several aspects of their function. Although further studies of ascorbate function in these cell types and in novel animal models are needed, available evidence generally supports a salutary role for this vitamin in ameliorating the earliest stages of atherosclerosis.     

Oxidative stress and endothelial dysfunction: therapeutic implications

In a previous issue of Annals of Medicine, we presented evidence in support of the concept that an abnormally increased production of reactive oxygen species plays a central role in the genesis and progression of cardiovascular disease. While a number of preclinical lines of evidence support this concept, and despite the results of many studies suggesting a beneficial impact of antioxidant drugs on endothelial function, large clinical trials have failed to demonstrate a benefit of antioxidants on cardiovascular outcomes. Studies exploring the possibility that classical antioxidants such as vitamin C, vitamin E, selenium, or folic acid may improve the prognosis of patients with cardiac disease have substantially reported neutral-and occasionally negative-results. In contrast, medications such as statins, ACE inhibitors, certain β-blockers, or angiotensin I receptor blockers, which possess indirect 'ancillary' antioxidant properties, have been associated with beneficial effects in both preclinical studies and large clinical trials. The reasons for the failure of the 'direct' approach to antioxidant therapy, and for the success of the therapy with these drugs, are discussed in the present review.