MiniReview |
-Tocopherol (Vitamin E)
From the Linus Pauling Institute, Oregon State University, Corvallis, Ore.
Correspondence to Balz Frei, PhD, Linus Pauling Institute, Oregon State University, 571 Weniger Hall, Corvallis, OR 97331-6512. E-mail balz.frei{at}orst.edu
| Abstract |
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-tocopherol (vitamin E) may
protect against atherosclerosis. These mechanisms
include inhibition of LDL oxidation and inhibition of leukocyte
adhesion to the endothelium and vascular
endothelial dysfunction. Overall, ascorbate appears to
be more effective than
-tocopherol in mitigating these
pathophysiological processes, most likely as a
result of its abilities to effectively scavenge a wide range of
reactive oxygen and nitrogen species and to regenerate
-tocopherol, and possibly tetrahydrobiopterin, from its
radical species. In contrast,
-tocopherol can act either
as an antioxidant or a pro-oxidant to inhibit or facilitate,
respectively, lipid peroxidation in LDL. However, this pro-oxidant
activity of
-tocopherol is prevented by ascorbate acting
as a coantioxidant. Therefore, an optimum vitamin C intake or body
status may help protect against atherosclerosis and its
clinical sequelae, whereas vitamin E may only be effective in
combination with vitamin C.
Key Words: ascorbic acid atherosclerosis endothelial cells low-density lipoprotein vitamin E
| Introduction |
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NAD(P)H Oxidase: Role in Cardiovascular Biology and Disease
Oxidant Signaling in Vascular Cell Growth, Death, and Survival
Potential Antiatherogenic Mechanisms of Ascorbate (Vitamin C) and
-Tocopherol (Vitamin E)
Crosstalk Between Nitric Oxide and Lipid Oxidation Systems: Implications for Vascular Disease Oxygen Radicals and Endothelial Dysfunction Vascular Oxygen Species Generation
David G. Harrison, Guest Editor
Oxidative stress is thought to play an important role in
atherosclerotic vascular disease.1 Thus, dietary
antioxidants such as ascorbate (vitamin C) and
-tocopherol (the chemically and biologically most active
form of vitamin E) can protect against the development and progression
of atherosclerosis in experimental
models.1 Numerous observational studies have shown an
inverse association between antioxidant intake or body status and the
risk of cardiovascular diseases.2 However,
several clinical trials, such as the recent GISSI and HOPE
trials, have found no benefits of vitamin E supplementation on
cardiovascular disease risk.3 A major
caveat with observational studies is that they can only show
associations and not causal relationships. Clinical trials have a
number of limitations, too, such as a relatively short period of
antioxidant treatment with a single dose only, and the fact that
antioxidant treatment of patients with advanced disease (secondary
prevention) may not provide information relevant to disease prevention
in healthy individuals (primary prevention). For example, both the
GISSI and HOPE trials were secondary prevention trials in which >75%
of all participants were treated with aspirin or other antiplatelet
agents, and many participants also received ß-blockers,
lipid-lowering agents, and calcium channel blockers.3 It
is doubtful whether vitamin E can exert beneficial effects above and
beyond these standard therapies. In addition, as explained in the
current article, vitamin E supplements alone may not be beneficial but
may have to be coadministered with vitamin C to effectively lower
oxidative stress. For further detailed discussions of the observational
and clinical trial data regarding vitamins C and E, see References
4 and 3 , respectively.
Understanding the specific mechanisms by which ascorbate and
-tocopherol exert their protective effects will help
elucidate their potential roles in atherogenesis and may ultimately
lead to successful preventive or therapeutic regimens. A number of
antiatherogenic mechanisms have been proposed, and of these several
will be discussed in this minireview. They include inhibition of LDL
oxidation by LDL-associated
-tocopherol or extracellular
ascorbate and inhibition of leukocyteendothelial
cell interactions and vascular dysfunction by both extracellular
and intracellular ascorbate and
-tocopherol.
| LDL Oxidation |
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-tocopheroxyl
radicals formed in the lipoprotein on attack by free radicals or other
reactive species8 9 (Figure 1A
-tocopherol can act as a pro-oxidant, rather than an
antioxidant, in LDL incubated in vitro8 9 (see below).
|
Ascorbate and LDL Oxidation
Human plasma and other extracellular fluids contain numerous
water-soluble antioxidants, including ascorbate, urate, bilirubin, and
various thiol compounds.10 Experimental data on the
effects of vitamin C supplementation of human subjects on ex vivo LDL
oxidation are sparse, mainly because ascorbate is removed from LDL
during isolation from plasma.11 However, there is
convincing evidence from in vitro studies that
physiological concentrations of ascorbate strongly
inhibit LDL oxidation by vascular cells and
neutrophils,12 13 as well as in cell-free
systems.14 15 Ascorbate prevents oxidative modification of
LDL primarily by scavenging free radicals and other reactive species in
the aqueous milieu.10 Thus, direct and rapid trapping of
these aqueous reactive species by ascorbate prevents them from
interacting with and oxidizing LDL. Ascorbyl radicals formed in this
process may be reduced back to ascorbate by dismutation, chemical
reduction (eg, by glutathione), or enzymatic reduction (eg, by
thioredoxin reductase).16 Dismutation also produces
dehydroascorbic acid, which in turn can be reduced back to ascorbate by
glutathione, thioredoxin reductase, and glutaredoxin.17
Ascorbate can also prevent the pro-oxidant activity of
-tocopherol by reducing the
-tocopheroxyl radical to
-tocopherol, thereby acting as a "coantioxidant" and
inhibiting LDL oxidation9 13 (Figures 1A
and 1B
).
-Tocopherol and LDL Oxidation
Human LDL contains various lipid-soluble antioxidants, including
-tocopherol,
-tocopherol, ubiquinol-10,
and several carotenoids and oxycarotenoids.13
-Tocopherol, the most abundant antioxidant in
LDL,13 can act as a chain-breaking antioxidant by
scavenging highly reactive lipid peroxyl and alkoxyl radicals, which
otherwise would propagate the chain reaction of lipid peroxidation.
Esterbauer et al6 reported that
-tocopheroldepleted LDL is able to undergo rapid lipid
peroxidation, whereas LDL isolated from
-tocopherolsupplemented subjects exhibits increased
resistance to ex vivo copperinduced oxidation.18
However, various investigators have since reported that the resistance
of LDL to oxidation does not correlate with its vitamin E
content2 9 and that ubiquinol-10, not
-tocopherol, forms the first line of antioxidant defense
in human LDL.13 In particular, Bowry and
Stocker8 and Neuzil et al9 reported that
-tocopherol can act as a pro-oxidant in LDL via
-tocopheroxyl radicalmediated formation of lipid radicals (Figure 1A
). Accordingly, in vitro and in vivo enrichment of LDL with
-tocopherol accelerates rather than inhibits the initial
stages of LDL oxidation.8 These results do not refute a
role for
-tocopherol as an antioxidant in vivo, given
that coantioxidants, such as ascorbate19 and
ubiquinol-10,13 are present in the vascular
environment and can convert
-tocopherol from a
pro-oxidant into an antioxidant.9 13
| Cell Adhesion |
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Ascorbate and Cell Adhesion
Two recent human studies have investigated the role of ascorbate
in inhibiting cell-cell adhesion.23 24 Smokers have
decreased plasma levels of ascorbate, and monocytes isolated from
smokers exhibit increased adhesion to cultured
endothelial cells compared with monocytes isolated from
nonsmokers.23 24 Supplementation of smokers with 2 g/day
of vitamin C for 10 days elevated plasma ascorbate levels almost 2-fold
and significantly reduced monocyte adhesion to cultured
endothelial cells.23 This finding
indicates that upregulation of ligands on monocytes is inhibited by
ascorbate.23 In another study, however, supplementation of
smokers with 2 g of vitamin C 2 hours before isolation of
monocytes had no effect on ex vivo monocyte-endothelial
cell adhesion or endothelial ICAM-1 surface expression,
despite a >3-fold increase in serum ascorbate levels.24
The supplementation period in this study may have been too short to
affect intracellular ascorbate levels.
Several in vivo studies using intravital microscopy in hamsters have demonstrated an important role of ascorbate in inhibiting leukocyteendothelial cell interactions induced by cigarette smoke25 26 or oxidized LDL,27 likely by antioxidant mechanisms. Lehr et al26 showed that the induction of leukocyte adhesion to the vascular wall elicited by cigarette smoke is due to the formation of oxidatively modified lipids with platelet-activating factorlike activity. Administration of ascorbate prevented the accumulation of these platelet-activating factorlike lipids and the subsequent leukocyteendothelial cell interactions.26
-Tocopherol and Cell Adhesion
Cell culture studies have shown that pretreatment of
endothelial cells with
-tocopherol
inhibits cytokine or oxidized LDLinduced expression of
ICAM-1, VCAM-1, or E-selectin and decreases adhesion of monocytes to
these cells.28 29 30 31 Interestingly, Cominacini et
al30 found that both LDL-associated and cellular
-tocopherol are able to inhibit upregulation of ICAM-1
and VCAM-1 by endothelial cells exposed to oxidized
LDL.
-Tocopherol also decreased stimulus-induced
expression of ß1 and ß2
integrins on leukocytes and adhesion of these cells to cultured
endothelial cells.28 32 33 Ex vivo studies
in humans have shown an inverse correlation between serum
-tocopherol levels and ß1
integrin expression on monocytes,32 as well as decreased
ex vivo monocyte-endothelial cell
adhesion34 after supplementation with
-tocopherol. Another study, however, showed no effect on
monocyte adhesiveness after supplementation of
hypercholesterolemic patients with
-tocopherol.35
-Tocopherol could inhibit the expression of adhesion
molecules and subsequent cell-cell interactions either by directly
scavenging reactive oxygen species (ROS) or by inhibiting protein
kinase C (PKC) activation and associated ROS
production.36 Although one study found no change
in PKC activity in endothelial cells treated with
-tocopherol, despite decreased E-selectin
expression,29 other studies showed decreased PKC activity
paralleled by decreased ROS production in leukocytes
treated with
-tocopherol.32 34
Despite convincing evidence that
-tocopherol decreases
cell-cell adhesion in vitro and ex vivo, evidence is completely lacking
in vivo.25 27 37 For example,
-tocopherol
supplementation of hamsters had no effect on
leukocyteendothelial cell interactions induced by
cigarette smoke25 or oxidized LDL.27 More
studies are needed to determine whether
-tocopherol and
ascorbate exert a consistent inhibitory effect on
in vivo leukocyteendothelial cell interactions and to
further elucidate the underlying mechanisms.
| Endothelial NO Synthesis |
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Ascorbate and EDNO
Numerous clinical studies have consistently demonstrated
beneficial effects of vitamin C treatment on
endothelium-dependent vasodilation in individuals with
coronary artery disease or coronary risk factors
(reviewed in Reference 4 ). There are a number of
potential mechanisms underlying the salubrious effects of ascorbate on
endothelial function (Figure 2A
). First,
ascorbate may be decreasing the levels of superoxide radicals and
oxidized LDL,43 44 both of which react with and
inactivate NO.41 42 Because of the facile
reaction between superoxide and NO radicals, relatively high
concentrations of ascorbate (
10 mmol/L) are required to
effectively inhibit the reaction of NO with superoxide.44
Such concentrations are potentially achievable in plasma by
intra-arterial infusion4 or in the cytoplasm
as a result of cellular uptake of ascorbate.45 46 47
Ascorbate may indirectly enhance endothelium-dependent
vasodilation by sparing intracellular thiols,48 which in
turn stabilize EDNO through the formation of biologically active
S-nitrosothiols49 (Figure 2A
).
Reducing agents such as ascorbate have also been implicated in the
rapid release of NO from
S-nitrosothiols.50 Finally, Heller et
al46 and, more recently, Huang et al47 have
shown that physiological concentrations of
ascorbate increase the synthesis and biological activity of NO in
cultured endothelial cells by increasing intracellular
tetrahydrobiopterin (Figure 2B
). Thus, a very likely mechanism
by which intracellular ascorbate stimulates NOS activity is
regeneration of tetrahydrobiopterin from the trihydrobiopterin radical
(Figure 2B
). Such a mechanism of action of ascorbate would also
prevent NOS from leaking superoxide radicals (Figure 2B
).
-Tocopherol and EDNO
Animal studies have provided consistent evidence for a
beneficial effect of
-tocopherol on vasodilation, as
well as insight into underlying mechanisms. Supplementation of
cholesterol-fed rabbits with
-tocopherol
increased both the resistance of LDL to oxidation and agonist-induced
relaxation of thoracic aortas, whereas supplementation with
ß-carotene had no effect on LDL oxidizability yet did enhance
agonist-induced vasodilation.51 These results suggest that
ß-carotene and
-tocopherol act by increasing vascular
antioxidant status rather than LDL antioxidant status. In addition,
-tocopherol may act by non-antioxidant mechanisms. For
example, Keaney et al52 proposed that
-tocopherol acts in the vascular wall by inhibiting PKC
activation by oxidized LDL, hence inhibiting PKC-mediated
phosphorylation of endothelial cell
muscarinic receptors and enhancing agonist-induced NOS activation. In
contrast, supplementation of cholesterol-fed rabbits with
supraphysiological amounts of
-tocopherol profoundly impaired agonist-induced
aortic relaxation and also increased the extent of intimal
proliferation.52A The mechanisms for these adverse effects
of high doses of
-tocopherol are unclear, but they may
be related to the pro-oxidant activity of
-tocopherol in
LDL (see Figure 1A
).
A number of clinical studies have shown that
-tocopherol
increases endothelium-dependent vasodilation in
individuals with coronary risk factors.37 53 54 55 56
Two of these studies also showed a reduction in markers of lipid
oxidation.53 54 Other human studies, however, did not find
an effect of
-tocopherol supplementation on
endothelium-dependent vasodilation57 58 59
or on lipid peroxidation.57 59
Combinations of antioxidants may be of particular benefit because of
the possible synergistic interaction between ascorbate and
-tocopherol (see Figure 1B
). Of 4 studies in
which individuals with coronary risk factors were supplemented
with
-tocopherol in combination with
ascorbate,60 61 62 63 only 1 showed no effect on
agonist-induced vasodilation, despite a reduction in the susceptibility
of LDL to ex vivo oxidation.63
Taken together, these data indicate that ascorbate, alone or in
combination with
-tocopherol, enhances the synthesis and
biological activity of EDNO through several antioxidant mechanisms, in
particular regeneration of tetrahydrobiopterin.
-Tocopherol may improve EDNO levels via the inhibition
of PKC activity; however, in humans there are insufficient data to
conclude that long-term treatment with
-tocopherol alone
is beneficial.
| Summary |
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-tocopherol protect against atherogenesis by inhibiting
LDL oxidation, by impairing the production of ROS by vascular
cells, and by limiting the cellular responses to oxidized LDL, in
particular adhesion molecule expression and EDNO synthesis. Some of the
beneficial effects of
-tocopherol may be attenuated by
the pro-oxidant effects on lipid peroxidation in LDL. However, this
pro-oxidant activity of LDL-associated
-tocopherol is
counteracted by ascorbate present in plasma and the
arterial wall.10 19 Although the current
evidence is promising, more mechanistic and human in vivo studies are
needed to determine whether optimizing the dietary intake or body
status of vitamins C and E can help decrease atherosclerotic vascular
disease and its clinical sequelae.
| Acknowledgments |
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Received May 10, 2000; revision received July 19, 2000; accepted July 20, 2000.
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