Maturitas 67 (2010) 103107

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Maturitas
j our nal homepage: www. el sevi er . com/ l ocat e/ mat ur i t as
Review
Antioxidants: Benets and risks for long-term health
Daisaku Yoshihara, Noriko Fujiwara, Keiichiro Suzuki

Department of Biochemistry, Hyogo College of Medicine, 1-1 Mukogawa-cho, Nishinomiya, Hyogo 663-8501, Japan
a r t i c l e i n f o
Article history:
Received 28 April 2010
Received in revised form 2 May 2010
Accepted 2 May 2010
Keywords:
Antioxidants
Vitamins C and E
Polyphenols
Estrogen
Probucol
Deferoxamine
a b s t r a c t
The oxidative modication hypothesis postulates that oxidative stress is one of the major factors in aging
and the development of age-related disorders, including cardiovascular diseases. In this scenario, the
oxidative modication of lipids, proteins and nucleic acids in vascular walls contributes to the etiology
of cardiovascular disease, implying that consumption or therapeutic use of antioxidants could prevent
the onset of such pathological disorders. Because of this, a number of studies have been conducted to
address the question of whether cardiovascular diseases can be modulated by antioxidant treatment or
consumption. Although some of the earliest data, collected in animal studies and epidemiologic studies
have shown a measure of success, numerous clinical trials indicate that this approach is of minimal or no
benet. These conclusions represent a challenge to design more sensitive antioxidant trials in order to
conrmor alter these conclusions. The focus of this reviewis onthe benets anddisadvantages associated
with the use of antioxidants, such as vitamins C and E, polyphenols, or antioxidant therapies, including
hormone replacement therapy and iron reduction therapy, on overall vascular health.
2010 Elsevier Ireland Ltd. All rights reserved.
Contents
1. Introduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 103
2. Antioxidants: derived from the diet . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 104
2.1. Ascorbic acid (vitamin C) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 104
2.2. Vitamin E . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 104
2.3. Polyphenols. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 105
3. Antioxidants for therapeutic use . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 105
3.1. Estrogen and hormone replacement therapy (HRT) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 105
3.2. Probucol . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 105
3.3. Deferoxamine and iron reduction therapy. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 106
4. Conclusion. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 106
Contributors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 106
Competing interests . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 106
Provenance. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 106
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 106
1. Introduction
Oxidative stress caused by the accumulation of reactive oxygen
species (ROS) in the body appears to be involved in a variety of
pathological processes including cardiovascular diseases, cancer,
neurodegenerative disorders and aging. Cardiovascular disease,
involving atherosclerosis and hypertension, is one of the leading
causes of death in advanced countries. The oxidative modication
hypothesis postulates that the nonspecic modication of lipids,

Corresponding author. Tel.: +81 798 45 6357; fax: +81 798 46 3164.
E-mail address: suzuki@hyo-med.ac.jp (K. Suzuki).
proteins, and nucleic acids in the vascular wall contributes to the
etiology of certain diseases, including atherosclerosis, eliminating
or minimizing these modications could minimize the develop-
ment of atherosclerosis. The natural antioxidant system in our
bodies consists of a series of antioxidant enzymes (e.g. superox-
ide dismutase and glutathione peroxidase), numerous endogenous
antioxidant molecules (e.g. glutathione and cysteine) and antioxi-
dant supplements (e.g. vitamins C and E). Antioxidants can also be
obtained from the diet in the form of vegetables, fruits, green tea
and chocolates. A number of clinical trials have been conducted,
in attempts to address the question of whether cardiovascular dis-
eases can be modulated by antioxidant treatment or consumption
[1,2]. Some of the earliest data were collected in animal studies
0378-5122/$ see front matter 2010 Elsevier Ireland Ltd. All rights reserved.
doi:10.1016/j.maturitas.2010.05.001
104 D. Yoshihara et al. / Maturitas 67 (2010) 103107
and indicated that antioxidants derived from dietary sources may
reduce the progression of atherosclerosis, and observational data
collected in humans suggest that the ingestion of antioxidants is
associated with preventing cardiovascular disease. However, con-
clusions reached in some clinical trials suggest that antioxidants
appear to have little or no benet. However, a lack of benecial
effects does not disprove the central role of oxidative stress in car-
diovascular diseases. On the contrary, these trials have stimulated
us to design better antioxidant trials in the future.
In this review, we focus on the benets and disadvantages of
the therapeutic use of antioxidants for vascular health and provide
some suggestions for how to use these antioxidants effectively in
terms of achieving long-term health.
2. Antioxidants: derived from the diet
Some dietary constituents have been suggested to function as
antioxidants. In vitro studies have shown that vitamin C or E and
polyphenols inhibit the generation of free radicals, as well as lipid
peroxidation and DNA damage.
2.1. Ascorbic acid (vitamin C)
Ascorbic acid (vitamin C), a water-soluble antioxidant produced
byplants andsomeanimals, functions tomaintainredoxhomeosta-
sis. Unlike other animals, humans are unable to synthesize vitamin
C due to the lack of the enzyme gulonolactone oxidase, which cat-
alyzes thenal stepinthesynthesis of vitaminC. Therefore, humans
must obtain vitamin C from natural sources or supplements in the
ordinary diet.
Several studies have been conducted, in an attempt to verify
the hypothesis that vitamin C plays a protective role in the pre-
vention of cardiovascular oxidative stress. The National Health and
Nutrition Examination Surveys (NHENES) reported that lowserum
levels of vitamin C were marginally associated with an increased
risk of fatal cardiovascular disease andsignicantly associatedwith
an increased risk for all-causes of mortality [3,4]. In contrast, the
HealthProfessionals Follow-upStudy, the Nurses HealthStudy, and
Iowa Womens Health Study did not nd evidence for a protective
effect of vitamin C against cardiovascular disease [57].
Because vitamin C levels in healthy subjects on a good diet are
normally sufcient to exert maximum antioxidant effects, vitamin
Cintake fromsupplements may conrmno further benets. Hence,
direct evidence of vitamin C as an in vivo antioxidant is limited.
On the other hand, lower vitamin C levels found in elderly peo-
ple, diabetic patients and cigarette smokers are most likely due to
increased oxidative stress. Smoking is a prominent risk factor for
cardiovascular disease because cigarette smoke induces endothe-
lial dysfunction via oxidative stress. Therefore, the supplemental
intake of vitamin C is thought to be useful in preventing the vascu-
lar damage that results from smoking. Mller et al. showed that
vitamin C supplementation (500mg/day) decreased the steady-
state level of oxidative DNAdamage inmononuclear blood cells [8].
On the other hand, hemodialysis patients also have a net decrease
in water-soluble antioxidants during the dialysis session, as the
result of loss of lowmolecular compounds by diffusion. Ramos and
Martnez-Castelao reported that the long-termsupplementation of
vitamin C at a level of 1g/day suppressed the increase in LDL oxida-
tionafter hemodialysis, however, vitaminCsupplementationfailed
to prevent steady-state levels of lipid peroxidation in hemodialysis
patients [9].
Overall, there is some encouraging but not overwhelming sup-
port for vitamin C as a protective factor against cardiovascular
diseases.
2.2. Vitamin E
Vitamin E is a fat-soluble antioxidant, and is generally thought
to be the most important inhibitor of lipid peroxidation. There are
some reports showing that vitamin E intake prevents the gener-
ation of free radicals. Rats receiving vitamin E supplementation
showed a decreased level of urinary peroxidation products [10].
Vitamin E supplementation signicantly increased plasma HDL-C
levels in rabbits that were fed a high cholesterol diet [11]. In adult
women, the consumption of antioxidant rich fruit and vegetables
is reported to be negatively associated with DNA damage [12]. The
Nurses Health Study showed that supplemental vitamin E use for
>2years resultedinlower predictedcardiovascular disease risk, but
this benecial effect was lost at lower doses and for shorter periods
of use [13]. The oral administration of vitamin E in hemodialy-
sis patients results in a signicant decrease in oxidized LDL, total
cholesterol and LDL-C levels [14].
On the basis of laboratory evidence and epidemiologic ndings,
numerous clinical trials have been conducted to assess the effects
of vitaminEsupplements. Randomized, blindedplacebo-controlled
trials were conducted, to assess the effects of vitamin E in the pri-
mary and/or secondary prevention of cardiovascular diseases. The
Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) study
was designed to determine whether vitamin E (50mg/day, 75IU)
and beta-carotene (20mg/day), either alone or in combination,
resulted in a decrease in the incidence of lung cancer approxi-
mately 30,000 male, Finnish smokers aged 5069 years. Although
the risk of lung cancer was increased in the beta-carotene group,
supplementation with vitamin E had a marginal effect on the inci-
dence of fatal coronary heart disease but had no effects on nonfatal
myocardial infarction [15,16]. Furthermore, several secondary pre-
vention trials have been performed using patients with a history of
cardiovascular disease. The randomized placebo-controlled study
using an intervention of vitamin E (800IU/day) versus a placebo
showed that vitamin E supplementation signicantly reduced the
risk of nonfatal myocardial infarctions [17]. On the contrary, the
Heart Outcomes Prevention Evaluation (HOPE) trial assessed vita-
min E and an angiotensin-converting enzyme inhibitor in high-risk
cardiovascular event subjects who had diabetes mellitus and at
least one other additional cardiovascular disease risk. The results
showed no signicant benets in the case of the vitamin E inter-
ventiongroup[18]. Negative results were alsoreportedinthe Heart
Protection Study, a double-blind, placebo-controlled, 22 facto-
rial trial, which compared antioxidant vitamin supplementation
(600mg vitamin E, 250mg vitamin C, and 20mg beta-carotene
daily) with a placebo using approximately 20,000 cardiovascular
high-risk patients. Although antioxidant treatment substantially
increased blood vitamin concentrations, it failed to demonstrate
benecial effects for cardiovascular protection. A meta-analysis
including 15 clinical trials on cardiovascular disease outcomes
failed to show benets for antioxidants against cardiovascular
disease outcomes. This analysis included 8 studies of vitamin E
(50800IU/day) andmost trials inthis analysis included>1000par-
ticipants. Unfortunately, a lack of efcacy was shownacross a range
of doses, different types and degrees of cardiovascular disease, and
in various populations of men and women [19]. Taking the above
collective information into account, primary and secondary pre-
vention trials do not support the clinical utility of vitamin E as an
antioxidant that reduces the burden of cardiovascular disease.
Although vitamin E inhibits lipid peroxidation, the addition
of excess vitamin E to lipid emulsions can accelerate lipid per-
oxidation in vitro [20]. In vivo studies also showed that the
administration of vitamin E raised plasma lipid peroxidation prod-
uct levels insmokers ona high-fat diet andincreasedthe fat content
of livers in rats that were fed a high-fat diet plus ethanol [21]. A
high intake of vitamin E in adults is generally thought to have only
D. Yoshihara et al. / Maturitas 67 (2010) 103107 105
minimal toxicity, but blood coagulation can be affected by virtue of
interfering with the action of vitamin K. Moreover, Miller et al., in
a meta-analysis, showed that high-dosage vitamin E supplements
might increase overall mortality in the general population [22].
These results suggest that high-dosages of vitamin E supplements
have the potential to be harmful.
2.3. Polyphenols
A polyphenol is any compound that contains more than two
OHgroups attachedtoa benzene ring. Polyphenols are alsowidely
distributed in our diet: vegetables, fruits and beverage such as
wine, cocoa and tea, and are consumed daily by most people, all
contain polyphenols. Polyphenols are divided into several classes
according to the number of benzene rings they contain and by the
structural elements that bind these rings to one another. The main
groups of polyphenols are: avonoids (e.g. anthocyanins, catechins
and isoavones), phenolic acids, phenolic alcohols, stilbenes (e.g.
resveratrol) and lignans.
Experimental evidence exists to suggest that polyphenols may
have antioxidant activity and may protect cells against oxidative
stress. In fact, it has been shown that cocoa and polyphenols in
wine prevent and/or inhibit the LDL oxidation, which is a key event
in the development of atherogenesis. In vitro studies show that
LDL-bound polyphenols increase the resistance of LDL to oxidation
and glycation [23]. Studies using rat liver microsomes showed that
resveratrol and its analogues inhibited ferrous/ascorbate-induced
lipid peroxidation in a dose-dependent manner [24]. These data
are partly supported by studies in laboratory animals, which indi-
cate that polyphenols may inhibit the oxidation of LDL, as well
as other biomarkers of lipid peroxidation. Studies using hyperc-
holesterolemic rabbits suggested that polyphenols in cocoa might
prolongLDLoxidationlagtimes anddecreasetheareaof atheroscle-
rotic lesions in the aorta [25]. Arecent study demonstrated that red
wine polyphenols, especially delphinidin, enhanced endothelium-
dependent relaxation via estrogen receptor activation followed by
nitric oxide signaling [26].
Some studies in humans suggest that polyphenols prevent
the oxidation of LDL [27]. Furthermore, several studies indicated
that polyphenols decreased TBARS and F2-isoprostans, biomarkers
of lipid peroxidation, and caused an increase in plasma HDL-
cholesterol levels as the result of the consumption of cocoa
polyphenols [28,29]. The consumption of cathechin in the form of
green tea reduced MDA-LDL concentrations without any signi-
cant decrease in plasma LDL-cholesterol concentrations in healthy
subjects [30].
Flavonoids are not only antioxidants but they also exert many
other effects in vitro. For example, the ingestion of red wine
polyphenols slowed atherosclerosis without affecting lipid peroxi-
dation, suggestive of a different mechanism[31]. Supplementation
with a mixture of cathechin, caffeic acid and resveratrol signif-
icantly decreased atherosclerosis in ApoE KO mice by affecting
the recruitment of inammatory cells and the expression of pro-
inammatory chemokines in the vascular wall [32].
3. Antioxidants for therapeutic use
3.1. Estrogen and hormone replacement therapy (HRT)
It is well known that women live longer than men on aver-
age in advanced countries. This distinction has been attributed,
at least in part, to the protective effect of female sex hormones
before menopause. For example, although male mice developed
diabetes when treated with streptozotocin, female mice were not
affected by the same treatment. In addition, estrogen treatment
protectedagainst streptozotocindiabetogenic effects inbothmales
and ovariectomized females [33]. Female sex hormones can exhibit
antioxidative activity in vitro because of the presence of phenolic
OH groups on the molecules. Thus, many therapies using female
sex hormones have been tested, in attempts to assess their antiox-
idative effects.
Short-term hormone replacement therapy (HRT, usually using
conjugatedestrogen+progestin) resultedina decrease inthe levels
of lipid peroxidation, as measured by F2-isoprastanes in humans
[34]. HRT may be a useful treatment in women who have a low
antioxidant activity. For example, estrogen increased the total
antioxidant activity and prevented lipid peroxidation in ovariec-
tomized women, especially in subjects who have the Q allele of
paraoxonase 1 (PON1) Q192R polymorphism [35]. Observational
studies alsoshowedthat HRTreducedcoronaryheart disease(CHD)
in postmenopausal women [36]. In the Womens Health Initiative
(WHI) randomized controlled trial, however, HRT after many years
of estrogen deprivation showed an increase in CHD events with
estrogen plus progestin in an older age group [37]. In 2002, a WHI
estrogen plus progestin trial was halted after a mean of 5.2 years
of follow-up because the health risks exceeded the benets. In
contrast, the WHI estrogen alone trial was continued. A subgroup
analysis of WHI indicated that women in whom estrogen-only
therapy was initiated at a young age (<60 years) or earlier post-
menopausal tended to show benecial effects of CHD prevention
and a reduced total mortality [38,39], but subjects who were sub-
jected to estrogen deprivation for many years (over 60 years) the
protective effect of CHD with hormone treatment was not demon-
strated [40].
Possible reasons for the apparent paradox in the benecial
vascular effects of hormone therapy in young women versus unfa-
vorable effects in older women have been widely discussed in the
literature. Some authors have advocated the following hypoth-
esis: estrogen signaling pathways are altered in older women
in a manner that converts vasoprotective effects to vasculotoxic
effects [41,42]. On the other hand, Marfella et al. showed a
potential benet of menopausal hormones even in a setting of
established atherosclerosis. Atherosclerotic plaques from internal
carotid arteries of postmenopausal women who had received HRT
contained fewer inammatory leukocytes, lower levels of tumor
necrosis factor (TNF)-andlower levels of activatednuclear factor-
B (NF-B) via the suppression of oxidative stress-dependent
ubiquitinproteasome overactivity compared to plaques from
untreated women [43]. These ndings suggest a novel mecha-
nism in which menopausal hormones reduce oxidative stress and
ubiquitinproteasome activity mediates inammatory activity in
atherosclerotic plaques of menopausal hormone-replaced women.
Clinical studies have raised many important questions concern-
ing the effects of hormone therapy on arteriosclerosis that cannot
easily be veried in human subjects. Therefore, further studies are
needed to clarify the molecular mechanism, based on fundamental
insights.
HRT could be a benecial treatment for women in terms of pro-
tecting against oxidative stress and reducing the development of
cardiovascular disease. However, hormone therapy should be used
as a short-term treatment for menopausal symptoms in cases of
younger women (<60 years) or an earlier postmenopausal period,
but not for the long-term prevention of cardiovascular disease.
3.2. Probucol
Probucol [4,4

-[(1-methylethylidene)bis(thio)]bis-[2,6-bis(1,1-
dimethylethyl) phenol]], is a well knowncholesterol-loweringdrug
and a chain-breaking antioxidant. Probucol has antiatherosclerotic
effects in vivo as well as antioxidant properties in vitro, although
the latter may not explain the former.
106 D. Yoshihara et al. / Maturitas 67 (2010) 103107
In hypercholesterolemic rabbits, probucol prevented the oxi-
dation of LDL and improved the atherosclerotic area in aortic
arches without affectingserumcholesterol levels [44]. TheProbucol
Angioplasty Restenosis Trial (PART) showed that probucol, when
administered beginning 4 weeks before percutaneous translumi-
nal coronary angioplasty, appears to reduce restenosis rates [45].
Yamashita et al. reported that long-term probucol treatment pre-
vents secondary attacks in a higher cardiovascular risk population
of familial hypercholesterolemia. These preventive effects appear
to be dependent on the antioxidant properties of the molecule
and on the activation of reverse cholesterol transport [46]. AGI-
1067 (succinobucol), the monosuccinic acid ester of probucol, is
a metabolically stable compound that has greater intercellular
antioxidant efcacy in vitro than probucol without its associated
QT-interval proronging effect [47,48]. Tardif et al. showed that AGI-
1067 reduces glycated hemoglobin levels and new-onset diabetes
in a clinical trial. Crim et al. recently demonstrated that AGI-1067
enhances glucose-stimulated insulin secretion and protects islets
against cytokine-induced cell death in vitro [49]. Therefore, AGI-
1067 may have potency as an antidiabetic agent on pancreatic
islets.
3.3. Deferoxamine and iron reduction therapy
Iron is an essential trace element for cells because it is required
for the biosynthesis of many molecules that contain a heme moi-
ety, as well as nonheme proteins. However, iron also participates in
diverse pathological processes by virtue of its ability to catalyze the
formation of ROS. Several studies showed that iron accumulation is
observed in pathologic lesions of arteriosclerosis, cancer and neu-
rodegenerative disorders. Findings from animal models and from
human studies provide support for the concept that elevated tis-
sue iron levels play a signicant role in the pathogenesis of these
disorders.
Some chelating agents have been used, in attempts to inhibit
iron-dependent oxidative damage. Deferoxamine is an iron chela-
tor and inhibits iron-dependent lipid peroxidation. Yoshihara et
al. reported that iron is deposited in Cu, Zn-superoxide dismu-
tase lacking mice kidneys [50] and that the malignant effects of
iron deposition is moderated by the administration of deferoxam-
ine (unpublished data). Therefore, deferoxamine could function as
a powerful iron chelator in vivo. In fact, deferoxamine is widely
used for the prevention and treatment of iron overload in patients
who have ingested toxic oral doses of iron or in hemochromatosis
patients.
Thepotential benet of ironreductiontherapywas alsoassessed
in the secondary prevention of cardiovascular disease. Findings of
the Iron (Fe) and Atherosclerosis Study (FeAST), the rst random-
izedtrial of ironreductiontherapy inelderly (4387 years) patients
with established peripheral vascular disease have been reported.
Although no overall statistically signicant cardiovascular benet
was found, there were highly signicant reductions in all types of
mortality and in combined deaths plus nonfatal myocardial infarc-
tions and strokes in association with iron reduction therapy in
subjects of the youngest quartile (4361 years) at entry [51]. The
improved survival in younger patients suggests that iron reduc-
tion with lower iron-storage targets and beginning at an earlier age
might prove more benecial. Further studies are needed to demon-
stratethat areductionof ironis indeedakeyfactor intheprevention
cardiovascular disease.
4. Conclusion
As discussed above, even though many antioxidants such as
vitamins C and E show strong positive effects in the laboratory
and epidemiological studies, their benecial effects appear to be
negligible, as evidenced by prospective controlled clinical trials
for the primary or secondary prevention of cardiovascular disease
events. A large body of evidence suggests that more strict clini-
cal trial designs will be necessary to effectively assess the utility
of antioxidants and that a multifaceted antioxidant approach to
atherosclerosis may produce optimal clinical rewards. ROS produc-
tion in our bodies is unavoidable, and hence the use of antioxidants
may be very important in preventing, reversing, or delaying the
onset of pathological disorders. However, at the present time, no
practical antioxidants are available for therapeutic use. Further
studies aimed at identifying the molecular mechanismfor the pro-
tection afforded by various antioxidants against oxidative-induced
vascular damage are needed, if antioxidants are to be used in a
clinical setting.
Contributors
Daisaku Yoshihara was involved in the literature search and
writing the rst draft. Noriko Fujiwara and Keiichiro Suzuki
were involved in rewriting and completing the manuscript,
respectively.
Competing interests
The authors declare that they have no competing interests.
Provenance
Commissioned and externally peer reviewed.
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