Anti-atherogenicity of nutritional antioxidants

Epidemiological studies have indicated that fruit- and vegetable-rich diets play a protective role against cardiovascular disease. An explanation for this protection lies in the presence of antioxidant vitamins in fruits and vegetables. A large number of studies have provided data suggesting that consumption of dietary antioxidants is associated with reduced risk for cardiovascular disease. Plausible mechanisms by which these antioxidants may reduce the development of atherosclerosis include inhibition of low-density lipoprotein (LDL) oxidation, cellular lipid peroxidation and cell-mediated oxidation of LDL, and reduction in blood cholesterol levels. This review reports on the recent data of the anti-atherosclerotic effects and mechanistical aspects of three major groups of dietary antioxidants: vitamin E, carotenoids and flavonoids.     

Role of antioxidants in atherosclerosis: epidemiological and clinical update

Low density lipoprotein (LDL) oxidative modification in the vascular wall seems to be a key factor in atherosclerosis development. Oxidised LDLs might recruit monocytes and favour their transformation into foam cells through a receptor-mediated intake (scavenger pathway). Moreover oxidised LDLs show cytotoxic potential which is probably responsible for endothelial cell damage and macrophage degeneration in the atherosclerotic human plaque. Following the oxidation hypothesis of atherosclerosis the role of natural antioxidants, i.e. Vitamin C, Vitamin E and carotenoids, has been investigated in a large number of epidemiological, clinical and experimental studies. Animal studies indicate that dietary antioxidants may reduce atherosclerosis progression, and observational data in humans suggest that antioxidant vitamin ingestion is associated with reduced cardiovascular disease, but the results of randomised controlled trials are mainly disappointing. It has been suggested that natural antioxidants may be effective only in selected subgroups of patients with high levels of oxidative stress or depletion of natural antioxidant defence systems. The favourable effects shown by some studies relating antioxidant dietary intake and cardiovascular disease, may have been exerted by other chemicals present in foods. Flavonoids are the ideal candidates, since they are plentiful in foods containing antioxidant vitamins (i.e. fruits and vegetables) and are potent antioxidants. Tea and wine, rich in flavonoids, seem to have beneficial effects on multiple mechanisms involved in atherosclerosis. Future studies should probably select patients in a context of high-oxidative stress / low-antioxidant defence, to verify if antioxidants may really prove useful as therapeutic anti-atherosclerotic agents.     

Free radicals and antioxidants in cardiovascular disease

Several lines of evidence suggest that free radical-mediated oxidative damage to lipoproteins may be an important factor predisposing them to uptake into the vascular wall. This has led to interest in the factors that determine the susceptibility of lipoproteins to oxidation and their relationship to the development of coronary heart disease. Of these factors, the lipoprotein content of natural antioxidant vitamins such as vitamin E, and beta-carotene have aroused particular interest. Studies in animal models of atherosclerosis suggest that natural and synthetic antioxidants can retard the development of atheroma. Epidemiological comparisons between populations and studies within populations also support the contention that high plasma levels or dietary intake of natural antioxidant vitamins may protect against the development of coronary disease in man. Prospective randomized controlled trials of antioxidants in high risk groups are underway to test whether the theoretical promise of a beneficial role for antioxidants in coronary heart disease prevention will be fufilled.     

Design and synthesis of 4,6-di-tert-butyl-2,3-dihydro-5-benzofuranols as a novel series of antiatherogenic antioxidants

Antioxidants have been considered as potential antiatherogenic agents by inhibiting oxidation of low-density lipoprotein (LDL), albeit vitamin E, a natural antioxidant, has failed to show reduction on atherosclerosis in clinical trials. We have rationally designed and synthesized a novel series of antioxidants, 4,6-di-tert-butyl-2,3-dihydro-5-benzofuranols, to overcome the clinical limitation of vitamin E. In vitro, the compounds showed a potent inhibitory effect on lipid peroxidation detected as 2-methyl-6-(p-methoxyphenyl)-3,7-dihydroimidazo[1,2-a]pyrazin-3-one (MCLA)-dependent chemiluminescence in linoleic acid autoxidation. They also inhibited the LDL oxidation induced by Cu(2+), and the inhibition is more potent than that of vitamin E and probucol. In vivo, 4,6-di-tert-butyl-2,3-dihydro-2,2-dipentyl-5-benzofuranol (BO-653, 1f), an optimal compound, showed the highest concentration in plasma and LDL fraction in Watanabe heritable hyperlipidemic rabbits, due to its high affinity to LDL. The isolated LDL samples from the 1f-treated rabbits showed potent resistibility to LDL oxidation. Compound 1f has been taken into clinical trials.     

Effects of antioxidants on vascular health

Substantial in vitro and animal model evidence implicates the free radical-mediated oxidation of low density lipoprotein and its subsequent preferential uptake by macrophages in the arterial intima as an important factor in the development of vascular disease. In addition, antioxidants which prevent the oxidation of LDL in vitro also reduce the severity of vascular disease in animal models. Although some epidemiological studies also suggest that inadequate antioxidant status is related to the development of vascular disease, particularly cardiovascular disease, results from intervention trials have been contradictory. Whereas vitamin E may have a role in reducing the incidence of vascular disease, evidence is less strong for vitamin C, flavonoids and beta-carotene. Additionally, supplementation with some antioxidants such as beta-carotene may increase the incidence of cancer in high risk groups. Although increasing antioxidant intake is generally beneficial for health, this should perhaps be achieved by an increased dietary intake of antioxidant-rich foods rather than by use of supplements.     

Protective effects of Peganum harmala L. extract, harmine and harmaline against human low-density lipoprotein oxidation

Oxidative modification of low-density lipoprotein (LDL) particles has been implicated in the process of atherogenesis. Antioxidants that prevent LDL from oxidation may reduce atherosclerosis. We have investigated the protective effect of Peganum harmala-extract (P-extract) and the two major alkaloids (harmine and harmaline) from the seeds of P. harmala against CuSO4-induced LDL oxidation. Through determination of the formation of malondialdehyde (MDA) and conjugated diene as well as the lag phase, the extract (P-extract) and compounds were found to possess an inhibitory effect. Moreover, harmaline and harmine reduced the rate of vitamin E disappearance and exhibited a significant free radical scavenging capacity (DPPH*). However, harmaline had a markedly higher antioxidant capacity than harmine in scavenging or preventive capacity against free radicals as well as inhibiting the aggregation of the LDL protein moiety (apolipoprotein B) induced by oxidation. The results suggested that P. harmala compounds could be a major source of compounds that inhibit LDL oxidative modification induced by copper.     

Dietary antioxidants and paraoxonases against LDL oxidation and atherosclerosis development

Oxidative modification of low-density lipoprotein (LDL) in the arterial wall plays a key role in the pathogenesis of atherosclerosis. Under oxidative stress LDL is exposed to oxidative modifications by arterial wall cells including macrophages. Oxidative stress also induces cellular-lipid peroxidation, resulting in the formation of 'oxidized macrophages', which demonstrate increased capacity to oxidize LDL and increased uptake of oxidized LDL. Macrophage-mediated oxidation of LDL depends on the balance between pro-oxidants and antioxidants in the lipoprotein and in the cells. LDL is protected from oxidation by antioxidants, as well as by a second line of defense--paraoxonase 1 (PON1), which is a high-density lipoprotein-associated esterase that can hydrolyze and reduce lipid peroxides in lipoproteins and in arterial cells. Cellular paraoxonases (PON2 and PON3) may also play an important protective role against oxidative stress at the cellular level. Many epidemiological studies have indicated a protective role for a diet rich in fruits and vegetables against the development and progression of cardiovascular disease. A large number of studies provide data suggesting that consumption of dietary antioxidants is associated with reduced risk for cardiovascular diseases. Basic research provides plausible mechanisms by which dietary antioxidants might reduce the development of atherosclerosis. These mechanisms include inhibition of LDL oxidation, inhibition of cellular lipid peroxidation and consequently attenuation of cell-mediated oxidation of LDL. An additional possible mechanism is preservation/increment of paraoxonases activity by dietary antioxidants. This review chapter presents recent data on the anti-atherosclerotic effects and mechanism of action of three major groups of dietary antioxidants-vitamin E, carotenoids and polyphenolic flavonoids.     

The Antioxidant Vitamins: Impact on Atherosclerosis

Atherosclerosis, the great killer of Western society, probably is initiated when the balance of subendothelial lipoproteins and oxidation potential is upset. Oxidation products, especially oxidized low-density lipoprotein, set into motion the cascading of numerous pathways, culminating in the fibrous atherosclerotic plaque. The natural antioxidant system includes enzymes and vitamins A, E, and C. The lipophilic vitamins A and E protect the fatty acid components of lipoproteins and membranes, and vitamin C functions in the aqueous phase both directly and by regenerating oxidized vitamin E. In animal models, the antioxidant vitamins protect lipids and prevent atherosclerosis. Population studies suggest an inverse relationship between atherosclerosis and vitamin levels. Several observational studies and some clinical trials have demonstrated that antioxidant vitamin supplements may prevent atherosclerosis. Although approximately 20% of the United States population regularly consumes vitamin supplements, often in high doses, the antiatherogenic benefits of antioxidant vitamins remain unproved by clinical trials, and the long-term effects of megadose vitamins are yet undefined.     

Protection of low density lipoprotein oxidation at chemical and cellular level by the antioxidant drug dipyridamole.

1. The oxidative modification of low density lipoprotein (LDL) is thought to be an important factor in the initiation and development of atherosclerosis. Natural and synthetic antioxidants have been shown to protect LDL from oxidation and to inhibit atherosclerosis development in animals. Synthetic antioxidants are currently being tested, by they are not necessarily safe for human use. 2. We have previously reported that dipyridamole, currently used in clinical practice, is a potent scavenger of free radicals. Thus, we tested whether dipyridamole could affect LDL oxidation at chemical and cellular level. 3. Chemically induced LDL oxidation was made by Cu(II), Cu(II) plus hydrogen peroxide or peroxyl radicals generated by thermolysis of 2,2'-azo-bis(2-amidino propane). Dipyridamole, (1-10 microM), inhibited LDL oxidation as monitored by diene formation, evolution of hydroperoxides and thiobarbituric acid reactive substances, apoprotein modification and by the fluorescence of cis-parinaric acid. 4. The physiological relevance of the antioxidant activity was validated by experiments at the cellular level where dipyridamole inhibited endothelial cell-mediated LDL oxidation, their degradation by monocytes, and cytotoxicity. 5. In comparison with ascorbic acid, alpha-tocopherol and probucol, dipyridamole was the more efficient antioxidant with the following order of activity: dipyridamole > probucol > ascorbic acid > alpha-tocopherol. The present study shows that dipyridamole inhibits oxidation of LDL at pharmacologically relevant concentrations. The inhibition of LDL oxidation is unequivocally confirmed by use of three different methods of chemical oxidation, by several methods of oxidation monitoring, and the pharmacological relevance is demonstrated by the superiority of dipyridamole over the naturally occurring antioxidants, ascorbic acid and alpha-tocopherol and the synthetic antioxidant probucol.     

Combined oestrogen-progestogen replacement therapy does not inhibit low-density lipoprotein oxidation in postmenopausal women

AIMS: The use of oestrogen containing hormone replacement therapy (HRT) is related to a significantly reduced atherosclerotic cardiovascular risk in postmenopausal women. Oestrogen is thought to be antioxidant and may inhibit low-density lipoprotein (LDL) oxidation in vitro. We investigated the effect of combined oestrogen and progestogen HRT on LDL oxidation in postmenopausal women. METHODS: Eighteen healthy women were given oestrogen/progestogen, and the susceptibility of LDL to oxidation was measured as the level of autoantibody to oxidative modified LDL and the production of conjugated dienes during copper-dependent oxidation after 3 and 6 months HRT. The levels of vitamin E, the major antioxidant in LDL, were also measured. RESULTS: After HRT, the anti-oxidatively modified LDL antibody level remained unchanged [1.58+/-0.16, 0.10 (-0.10, 0.26), and 0.08 (-0.09, 0.19), mean+/-s.d. at baseline, and mean change with 95% confidence intervals for differences at 3 and 6 months, respectively, P>0.05] as did the production of conjugated dienes when determined as lag phase [51.2+/-7.5, -0.3 (-3.9, 3.3), and 1.5 (-3.4, 6.4) min, P>0.05]. The LDL vitamin E content, measured as alpha-tocopherol, was also not altered [2.34+/-0.54, -0.07 (-0.27, 0.13), and -0.07 (-0.33, 0.16) nmol mg(-1) LDL, P>0.05] by treatment. CONCLUSIONS: Combined oestrogen and progestogen therapy for 6 months in postmenopausal women does not protect LDL against oxidation.     

Effect of antioxidants on atherosclerotic plaque formation in balloon-denuded and irradiated hypercholesterolemic rabbits

The oxidative modification of low-density lipoprotein (LDL) hypothesis implies that antioxidants should be effective in suppressing atherosclerosis. This study is designed to test the potential of antioxidants to inhibit atherosclerotic plaque progression in balloon-denuded and irradiated hypercholesterolemic rabbits. Rabbits were fed with a 1% cholesterol diet supplemented with or without a mixture of antioxidants (vitamin E, vitamin C, selenium, zinc, copper, manganese, N-acetylcysteine, glutamine). At 7 days both iliac arteries were balloon denuded, and 4 weeks later, 1 iliac artery underwent endovascular irradiation (n=12), while the contralateral was sham treated (n=12). Four weeks after irradiation, animals were euthanized, and arteries were fixed and processed for histo- or immunohistochemistry for determining the plaque area, macrophage count, and oxidized LDL-positive areas. Plasma antioxidant levels were significantly higher in the animals fed with antioxidant diet. Plasma (thiobarbituric acid-reactive substances) and arterial tissue oxidized LDL (immunoreactive to specific oxidized LDL antibody) levels were significantly higher in the irradiated as compared with nonirradiated animals (0.69+/-0.09 and 31.05+/-4.21 versus 0.24+/-0.04 and 18.42+/-4.62, P<0.001 and 0.05), and antioxidants partially lowered the oxidized LDL levels (0.35+/-0.14 and 25.41+/-4.82, P<0.001 and 0.01). Plaque area in the irradiated animals was 175% greater than in nonirradiated animals (P<0.05). Antioxidant supplementation resulted in a 50% decrease in plaque area of both control and irradiated animals. Antioxidants reduced both the cholesterol-induced and radiation-enhanced circulating and tissue oxidized LDL levels, resulting in reduced plaque.     

Crocetin attenuates atherosclerosis in hyperlipidemic rabbits through inhibition of LDL oxidation

Oxidation of low-density lipoprotein plays a crucial role in the pathogenesis of atherosclerosis, raising the possibility of using antioxidants as an inhibitor of atherosclerosis. However, studies with antioxidants have led to contradictory results. In the present study, we investigated the effect of crocetin, a carotenoid with potent antioxidant activity, on experimental atherosclerosis in rabbits. After 8 weeks of feeding on high lipid diet, rabbits developed severe atherosclerotic lesions in thoracic aortas (P < 0.01), together with a significant elevation of plasma lipids level, thiobarbituric acid reactive substances (TBARS), and oxidized low-density lipoprotein (P < 0.01). In contrast, supplementation with crocetin markedly reduced the progression of atherosclerotic lesions (P < 0.01) and plasma levels of Ox-LDL and TBARS, whereas plasma lipids level remained unchanged. Plasma total antioxidant capacity and superoxide dismutase activity were obviously increased in crocetin-treated rabbits. In vitro studies demonstrated that supplementation with crocetin significantly increased the resistance of LDL to cupric ion-induced oxidation. Regression analysis indicated that atherosclerotic areas correlated positively with plasma level of Ox-LDL and the susceptibility of LDL to in vitro oxidation. These findings suggest that suppression of LDL oxidation by crocetin contributes, at least partly, to the attenuation of atherosclerosis.     

What we learnt from randomized clinical trials and cohort studies of antioxidant vitamin? Focus on vitamin E and cardiovascular disease

There is no doubt that oxidative stress is pivotally involved in the process of atherosclerosis. Thus antioxidants, particularly vitamin E, have been expected to retard the development of atherosclerosis. In fact, several cohort studies suggested reduced cardiovascular risk in persons taking vitamin E supplements. However, randomized clinical trials of vitamin E did not show any benefit of vitamin E supplementation in terms of prevention of coronary heart disease and death. Discrepancy between cohort studies and randomized clinical trials may be partly explained by difference in coronary risk in study participant. However, use of vitamin E supplementation in low risk population has not been justified yet.     

Oxidized low-density lipoprotein inhibits endothelium-dependent vasodilation by an antioxidant-sensitive,lysophosphatidylcholine-independent mechanism

Previous studies have shown that oxidized low-density lipoprotein (LDL) can impair endothelial function and that this can be overcome in vivo by administration of vitamin E. However, it is unclear whether this effect of oxidized LDL is due to lysophosphatidylcholine or other components of oxidized LDL, and it is also uncertain if the protective effect of vitamin E is related to its antioxidant action. The objectives of the current study were to define how much of the effect of extensively oxidized LDL on endothelium-dependent relaxation (EDR) was in fact due to lysophosphatidylcholine, to determine if the effect of oxidized LDL involved oxidant stress to the endothelium, and, if so, to ascertain if this could be blocked by oxyradical scavengers or antioxidants. Endothelial function was assessed by measuring vasodilation in preconstricted rat mesenteric artery rings in response to acetylcholine. In the presence of 100 microg/mL oxidized LDL, 25-fold higher concentrations of acetylcholine were required for the same degree of vasorelaxation. Similar concentrations of native LDL or acetyl LDL had no effect, but 100 microg/mL phospholipase A(2)-treated LDL or 20 microM lysophosphatidylcholine produced a similar inhibition of EDR. Removal of more than 90% of lysophosphatidylcholine from oxidized LDL did not affect its ability to inhibit EDR, nor did treatment of oxidized LDL with borohydride. This effect of oxidized LDL was blocked by preincubation of arterial rings with vitamin E, probucol, or BO-653 (a potent lipophilic antioxidant), but not by superoxide dismutase. In contrast, the inhibition of EDR by lysophosphatidylcholine was unaffected by antioxidants. Calphostin C prevented the inhibition of EDR by oxidized LDL and lysophosphatidylcholine. These studies demonstrate that at least part of the effect of oxidized LDL on EDR is independent of lysophosphatidylcholine, lipid peroxides, and superoxide release but appears to involve intracellular oxidative stress and protein kinase C activation.     

Antioxidant nutrients and lead toxicity

Lead-induced oxidative stress contributes to the pathogenesis of lead poisoning for disrupting the delicate prooxidant/antioxidant balance that exists within mammalian cells. Production of reactive oxygen species (ROS) is increased after lead treatment in in vitro studies. In vivo studies suggest that lead exposure causes generation of ROS and alteration of antioxidant defense systems in animals and occupationally exposed workers. The mechanisms for lead-induced oxidative stress include the effect of lead on membrane, DNA, and antioxidant defense systems of cells. From low to high doses of lead exposure, there are different responses of lead-induced oxidative stress in various target sites including lung, blood vessels, testes, sperm, liver, and brain in epidemiological as well as animal studies. Therefore, reducing the possibility of lead interacting with critical biomolecules and inducing oxidative damage, or bolstering the cell's antioxidant defenses might be associated with the beneficial role of antioxidant nutrients through exogenous supplementation of antioxidant molecules. Although many researchers have investigated the benefit of antioxidants in preventing lead toxicity, the mechanisms of antioxidant nutrients being effective via rebalancing the impaired prooxidant/antioxidant ratio are not completely clear. Antioxidant nutrients including, vitamin E, vitamin C, vitamin B(6), beta-carotene, zinc, and selenium, are addressed in this review to discuss their beneficial role in lead-induced oxidative stress.     

Thyronines and probucol inhibition of human capillary endothelial cell-induced low density lipoprotein oxidation

Oxidized lipoproteins have been implicated as important factors in the pathogenicity of atherosclerosis. Thus, antioxidants play a significant role in inhibiting a critical step in atheroma progression. Previously, we demonstrated that thyronine analogs inhibit Cu²⁺-induced low density lipoprotein (LDL) oxidation. In the present study, we examined the effect of thyronine analogs on endothelial cell (EC)-induced LDL oxidation. LDL was incubated with or without EC in the presence or absence of various concentrations of thyronine, vitamin C, or probucol at 37 ° in a humidified atmosphere (95% air, 5% CO₂). Thyronine analogs, probucol, and vitamin C inhibited EC-induced LDL oxidation in a concentration-dependent manner. The concentration of each agent (μM) producing 50% inhibition (ic₅₀) of EC-induced LDL oxidation for thiobarbituric acid reactive substances (TBARS) and electrophoretic mobility, respectively, was as follows: 0.294 and 0.417 for levothyroxine (l-T₄); 0.200 and 0.299 for l-triiodothyronine (l-T₃); 0.125 and 0.264 for dextro-thyroxine (d-T₄); 0.203 and 0.304 for reversed triiodothyronine (rT₃); 1.02 and 1.44 for probucol; and 13.6 and 14.9 for vitamin C. Thyroid binding globulin (TBG) inhibited EC-induced LDL oxidation; further, thyronines bound to TBG exhibited more antioxidant activity than unbound thyronines. Pretreatment of EC with any of the thyronines decreased the ability of EC to oxidize LDL. Also, our results showed that a synergistic interaction exists between vitamin C and T₄ in the inhibition of EC-induced LDL oxidation. The T₄ and TBG concentrations that inhibited LDL oxidation were in the physiological range. We conclude that T₄, like the pharmacological agent probucol, reduces oxidative modification of LDL and thus may act as a natural inhibitor of atherogenesis.     

丹酚酸-A体外对人血清低密度脂蛋白氧化修饰的抑制作用

目的研究丹酚酸-A(Sal-A)对人血清低密度脂蛋白(LDL)氧化修饰的抑制作用。方法用Cu²⁺体外诱导LDL过氧化,观察Sal-A对MDA,脂褐素和维生素E含量,氧化LDL电泳迁移率以及对LDL氧化过程中自由基的产生及Sal-A螯合Cu²⁺的作用。结果LDL经Cu²⁺诱导过氧化后,丙二醛和脂褐素的生成增加,维生素E含量下降,LDL电泳迁移速度加快,LDL氧化过程中自由基的生成增加。10^-6～10^-4 mol·L^-1 Sal-A可剂量依赖性地抑制上述改变,并且Sal-A能螯合Cu²⁺。结论丹酚酸-A可有效地抑制Cu²⁺诱导的人LDL氧化,该作用可能与其清除自由基及螯合铜离子的能力有关。     

Natural Antioxidants for the Prevention of Atherosclerosis

Hypercholesterolemia, cigarette smoking, hypertension, and obesity are known contributing risk factors for the development of atherosclerotic coronary artery disease (CAD). However, they account for only half of all cases of CAD, and the complete pathologic process underlying atherosclerosis remains unknown. Growing evidence suggests that oxidative modification of low-density lipoprotein (LDL) may be of particular importance in the pathogenesis. Oxidized LDL exhibits proatherogenic effects. Therefore, current research has focused on inhibiting the oxidation of LDL as a means of inhibiting the atherosclerotic process. One such approach is to enhance the endogenous antioxidant defense systems within the LDL particle with lipophilic antioxidants such as α-tocopherol and β-carotene, or by supplementing the aqueous-phase antioxidant capacity with ascorbic acid. Observational data suggest a protective effect of antioxidant supplementation on the incidence of CAD; however, specific doses cannot be recommended since the data are inconclusive.     

Antioxidants suppress plasma levels of lectinlike oxidized low-density lipoprotein receptor-ligands and reduce atherosclerosis in watanabe heritable hyperlipidemic rabbits

Oxidative modification of low-density lipoprotein (LDL) has been implicated in the pathogenesis of atherosclerosis. In this study, we investigated the effects of antioxidants including probucol, vitamin E, and fluvastatin, an HMG-CoA (hydroxy-3-methylglutaryl coenzyme A) reductase inhibitor with antioxidative property, on plasma levels of oxidized LDL (OxLDL) during the progression of atherosclerosis in Watanabe heritable hyperlipidemic (WHHL) rabbits. OxLDL were measured as ligand for lectin-like OxLDL receptor-1 (LOX-1). LOX-1-ligand was higher in WHHL rabbits than in control rabbits as early as 2 months of age and was sustained throughout the experimental period. Supplementation of probucol (1%) and vitamin E (0.5%) to the diet reduced LOX-1-ligand but had little effect on total cholesterol (T-CHO). Fluvastatin (0.03%) significantly reduced both LOX-1-ligand and T-CHO. The extent of reduction in T-CHO was less prominent than in the case of LOX-1-ligand. All of the agents reduced the atherosclerotic lesion area and lipid contents of aortic arches. These parallel results indicate that oxidatively modified LDL elevated in the early stages of atherogenesis is of functional importance in the progression of the disease and can be suppressed by antioxidant treatment. Furthermore, fluvastatin may reduce the evolution of atherosclerosis, not only by lowering plasma cholesterol but also by reducing oxidative modification of LDL.