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Vascular Biology Laboratory, Jean Mayer U.S. Department of Agriculture Human Nutrition Research Center on Aging at Tufts University, Boston, MA 02111
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONVitamin E and atherosclerosisMechanism of vitamin EREFERENCES |
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KEY WORDS: • 
-tocopherol • cardiovascular disease • atherosclerosis • molecular mechanism
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONVitamin E and atherosclerosisMechanism of vitamin EREFERENCES |
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Vitamin E, mainly -tocopherol, is the major fat-soluble
antioxidant present in the LDL particle. On average, 5–9 vitamin E
molecules are carried by each LDL particle and are believed to protect
LDL from oxidative damage. In vivo, free radicals generated by
endothelial cells of the arterial wall and activated macrophages are
thought to oxidize LDL particles (Carr et al. 2000
),
making them chemotactic to attract monocytes. The oxidized LDL
particles are recognized by macrophage scavenger receptors and taken up
by the macrophages, forming lipid-laden foam cells in the fatty
streak lesions. In vitro studies have indicated that increasing the
vitamin E content of LDL particles increases LDL resistance to
oxidation and decreases their uptake by macrophages. Vitamin E
supplementation has also been reported to suppress macrophage uptake of
oxidized LDL in human arterial lesions (Iuliano et al. 2000
). Vitamin E in LDL particles acts as a chain-breaking
antioxidant and prevents lipid peroxidation of polyunsaturated fatty
acids and modification of proteins in LDL by reactive oxygen species
(ROS) (Carr et al. 2000
).
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Vitamin E and atherosclerosis |
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TOPABSTRACTINTRODUCTIONVitamin E and atherosclerosisMechanism of vitamin EREFERENCES |
|---|
). Prospective cohort
studies in men and women also reported a lower risk of CVD with
long-term vitamin E supplementation (Rimm et al. 1993
, Stampfer et al. 1993
). The reduced
relative risk of death from heart disease has been reported also in
elderly subjects who were supplemented with vitamin E (Losonczy et al. 1996
). An inverse association between CVD and vitamin E
supplement usage (Meyer et al. 1996
) or vitamin E from a
food source (Kushi et al. 1996
) has also been reported.
Several other studies have found inverse association of blood vitamin E
with angina or myocardial infarction (Miwa et al. 1996
,
Riemersma et al. 1991
, Salonen et al. 1985
).
Earlier studies also reported that vitamin E helped to reduce
intermittent claudication (Haeger 1974
,
Livingstone and Jones 1958
, Tornwall et al. 1999
, Williams et al. 1971
). As clinical indices
of CVD, ultrasound measurements of intima-media thickness of the
carotid artery wall and angiographic scores of coronary artery stenosis
have been reported to be inversely related to vitamin E status
(Kirtchevsky et al. 1995
, Rengestrom et al. 1996
). High levels of vitamin E in RBC were associated with
less thickening of the arterial wall in French patients
(Bonithon-Kopp et al. 1997
) and low vitamin E status in
Eastern Finnish men who had accelerated atherosclerosis (Salonen et al. 1993
). In Finnish men who were heavy smokers, 50 mg/d of
synthetic vitamin E supplementation for 6 y provided a slight
protection against ischemic heart disease mortality (The Alpha-Tocopherol Beta-Carotene Cancer Prevention Study Group 1994
). These observational data are further supported by the
positive effect of vitamin E in high risk CVD patients. (Hodis et al. 1995)
reported that less progression of coronary lesion
was observed when patients received vitamin E supplements.
Supplementation with 400 or 800 IU/d natural vitamin E
substantially reduced the rate of nonfatal myocardial infarction, with
beneficial effects apparent after 1 y of supplementation
(Stephens et al. 1996
).
In contrast, two recent studies (GISSI and HOPE
trials)(GISSI-Prevenzione Investigators 1999
,
The Heart Outcomes Prevention Evaluation Study 1999
)
reported that vitamin E treatment of CVD patients had no effect on
reducing the primary end points, which included death, nonfatal
myocardial infarction or stroke. It was suggested that the genetic
background, type and dose of vitamin E and dietary habit and lifestyle
of study subjects might have contributed to the differential results in
these studies (Brown 1999
, Jialal et al. 1999
).
Although these two recent studies have raised some doubts on the efficacy of vitamin E in the prevention of progression of atherosclerotic lesions, the overwhelming observational and experimental studies strongly support its positive effect on the reductions of risk of atherogenesis. Investigators of the HOPE study suggested that a longer treatment time and follow-up might be necessary to suppress early events and observe a positive effect of vitamin E. In many observational studies in which the beneficial effects of vitamin E have been noted, intake of other vitamins and micronutrients and their interaction with vitamin E might have contributed to the observed positive effects. Accordingly, trials using a combination of vitamin E with other micronutrients are currently underway and will reveal the role of such interactions in the prevention or regression of atherosclerosis.
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Mechanism of vitamin E |
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TOPABSTRACTINTRODUCTIONVitamin E and atherosclerosisMechanism of vitamin EREFERENCES |
|---|
). Vitamin E inhibits production of proinflammatory cytokines by
endothelial cells and immune cells (Cannon et al. 1991
,
Devaraj et al. 1996
, Wu et al. 1999
).
Vitamin E suppresses expression of adhesion molecules on endothelial
cells and ligands on monocytes and reduces their adhesive interactions,
which is an important early event in the initiation of fatty streak
formation and atherogenesis. This interaction has been shown to be
reduced by vitamin E supplementation in cell culture systems and in
both animal and human studies (Devaraj et al. 1996
,
Fruebis et al. 1999
, Wu et al. 1999
).
Soluble adhesion molecules are regarded as a marker for
atherosclerosis. Vitamin E supplementation reduced production of
intracellular adhesion molecule-1 by endothelial cells (Martin et al. 1997
). Vitamin E may also inhibit production of
chemokines by endothelium, such as interleukin-8 and MCP-1 (Wu et al. 1999
), and reduce the attraction of monocytes to
inflammatory sites at the arterial wall. Modulation of cytokine release
and expression of adhesion molecules by vitamin E appears to be through
inhibition of ROS-sensitive signaling pathways, which include
protein kinase C and DNA-binding activity of nuclear transcription
factor-
B. Studies have also indicated that vitamin E may function
through its nonantioxidant properties to inhibit smooth muscle cell
proliferation (Ricciarelli et al. 1998
) and platelet
aggregation (Freedman et al. 1996
), which are important
processes in plaque formation and atherogenesis. Vitamin E also
modulates cyclooxygenase-2 activity and inhibits thrombaxane formation,
which has platelet aggregation and vasoconstrictive properties, and
increases production of prostacyclin, which has antiaggregatory and
vasodilatory properties (Chen et al. 1998
,
Meydani et al. 1993
). These effects of vitamin E
together with modulation of NO production by the endothelium can
modulate vascular reactivity in response to physical stress and thus
may contribute to the reduction of risk of ischemic heart disease
(Kinlay et al. 1999
, Newaz et al. 1999
).
In this symposium, the current understandings of several molecular and
cellular mechanisms by which vitamin E may exert its beneficial effects
in the prevention of atherogenesis will be reviewed.
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FOOTNOTES |
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2 This material is based on work supported by the U.S. Department of Agriculture, under agreement no. 58–1950-001. Any opinions, findings, conclusions, or recommendations expressed in this publication are those of the author(s) and do not necessarily reflect the view of the USDA.
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REFERENCES |
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|
TOPABSTRACTINTRODUCTIONVitamin E and atherosclerosisMechanism of vitamin EREFERENCES |
|---|
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Freedman J. E., Farhat J. H., Loscalzo J., Keaney J.F.J. Alpha-tocopherol inhibits aggregation of human platelets by a protein kinase C-dependent mechanism. Circulation 1996;94:2434-2440
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