![[Feedback]](/icons/banner/feedbackACT.gif){kind=icon}
![[For Subscribers]](/icons/banner/subscriberACT.gif){kind=icon}
![[Archive]](/icons/banner/archiveACT.gif){kind=icon}
![[Search]](/icons/banner/searchACT.gif){kind=icon}
![[Contents]](/icons/banner/tocACT.gif){kind=icon}
|
|
|
|
|
||
Department of Nutrition and Food Management, Linus Pauling Institute, Oregon State University, Corvallis, OR 97331-6512 and Division of Critical Care and Pulmonary Medicine, Department of Internal Medicine, University of California, Davis, School of Medicine, Sacramento, CA 95817
 |
ABSTRACT |
|---|
 TOP ABSTRACT INTRODUCTIONREFERENCES |
|---|
-tocopherol may play
a critical role in maintaining the function of key cellular components
in the atherosclerotic process through its ability to inhibit the
activity of protein kinase C, a key player in many signal transduction
pathways. -Tocopherol modulates pathways of platelet aggregation,
endothelial cell nitric oxide production, monocyte/macrophage
superoxide production and smooth muscle cell proliferation. Regulation
of adhesion molecule expression and inflammatory cell cytokine
production by -tocopherol has also been reported. More studies are
required to relate -tocopherol intakes to optimal tissue responses
in humans.
KEY WORDS: • -tocopherol • atherosclerosis • cytokine • adhesion molecule • platelet aggregation • nitric oxide • superoxide
|
INTRODUCTION |
|---|
|
TOPABSTRACTINTRODUCTIONREFERENCES |
|---|
), and, by extension,
antioxidants by their ability to quench free radicals and reactive
oxygen species, may have a beneficial role in modulating oxidative
damage and thereby decreasing risk of atherosclerotic lesion formation
and progression. As an example, studies in mice genetically susceptible
to atherosclerosis demonstrate that vitamin E supplementation decreases
both aortic lesion area and F2-isoprostanes
(Pratico et al. 1998
), a measure of lipid peroxidation,
in the artery wall. Moreover, atherosclerosis was more severe in mice
that were both genetically atherosclerosis susceptible and vitamin E
deficient, a result of knocking out the -tocopherol transfer protein
(-TTP) (Terasawa et al. 2000
).
The situation in humans is not quite so straightforward. LDL isolated
from subjects taking vitamin E supplements (
400 IU) is
less susceptible to ex vivo oxidation (Devaraj et al. 1997
, Fuller et al. 1996
, Jialal et al. 1995
). In epidemiologic studies, vitamin E supplement intakes
>100 IU/d for 2 y were associated with decreased risk of
heart attacks (Rimm et al. 1993
, Stampfer et al. 1993
). In one intervention study, vitamin E supplements given
to heart attack victims decreased the risk of subsequent nonfatal
myocardial infarction by 75% (Stephens et al. 1996
).
However, this latter observation was not reproduced in two other larger
trials (GISSI-Prevenzione Investigators 1999
, Yusuf et al. 2000
).
The question then, is how does vitamin E decrease heart attack risk?
Certainly, it is an antioxidant, and there have been a plethora of
studies demonstrating that vitamin E supplementation can decrease LDL
oxidation, when tested in vitro. The potential role of this antioxidant
activity has been called into question, however, because there is
vitamin E accumulated in the atherosclerotic lesion in humans
(Upston et al. 1999
).
Importantly, -tocopherol appears to modulate a variety of cellular
functions that are not necessarily a result of its antioxidant
activity. These functions may have potent effects in modulating heart
attack risk. For example, -tocopherol inhibits smooth muscle cell
proliferation (Boscoboinik et al. 1991
, Chatelain et al. 1993
, Clement et al. 1997
, Stauble et al. 1994
, Tasinato et al. 1995
) and thus may
decrease vascular wall thickening.
Another route by which -tocopherol may decrease heart attack risk is
through modulation of platelet function. Platelets form the thrombus
that occludes the vessel, causing the heart attack. -Tocopherol
inhibits platelet adhesion, aggregation and platelet release reactions
(Freedman et al. 1996
, Higashi and Kikuchi, 1974
, Ishizuka et al. 1998
, Steiner and Anastasi, 1976
). Moreover, vitamin E inhibits plasma generation
of thrombin, which binds to platelet receptors and induces aggregation
(Rota et al. 1998
). In human endothelial cells,
-tocopherol potentiates synthesis of prostacyclin, a potent
vasodilator and inhibitor of platelet aggregation (Chan and Leith, 1981
, Szczeklik et al. 1985
,
Thorin et al. 1994
, Tran and Chan, 1990
).
Inflammation is increasingly recognized as a central component in
vascular dysfunction. Monocytes are key players; they invade the
injured intima and cause LDL oxidation and further inflammation.
-Tocopherol decreases monocyte adhesion to the endothelium by
down-regulating expression of adhesion molecules (Devaraj et al. 1996
, Faruqi et al. 1994
, Islam et al. 1998
, Martin et al. 1997
, Molenaar et al. 1989
). -Tocopherol also decreases monocyte superoxide
production (Cachia et al. 1998
, Islam et al. 1998
) and thereby potentially decreases the production of
oxidized lipids. -Tocopherol is involved in modulating the
inflammatory response because it decreases interleukin-1ß release
from monocytes by inhibiting 5-lipoxygenase (Devaraj and Jialal, 1999
). -Tocopherol enrichment of endothelial cells in
culture inhibits the expression of intercellular cell adhesion
molecule-1 and vascular adhesion molecule-1 induced by exposure to
oxidized LDL (Cominacini et al. 1997
). -Tocopherol
also mediates up-regulation of the expression of cytosolic
phospholipase A2 and cyclooxygenase (Chan et al. 1998a
and 1998b
, Tran et al. 1996
).
Another key function that vitamin E regulates is vascular homeostasis.
It is well appreciated that normal vascular function requires
responsiveness to NO. Through its action on protein kinase C in
endothelial cells, -tocopherol has been shown to mediate NO
(Keaney et al. 1999
). In an ex vivo study of rabbit
aorta, delivery of -tocopherol, mediated by plasma phospholipid
transfer protein, resulted in the maintenance of relaxation in response
to acetylcholine.
It would appear that although a specific role in a required metabolic
function has not been found for -tocopherol, these newly described
functions may be critical in humans for the prevention of various
chronic diseases. The new recommended dietary allowances (RDA) for
vitamin E have just been published by the Institute of Medicine (NRC
2000
). Unfortunately, none of the described -tocopherol functions
have been sufficiently explored to be used as markers for establishing
requirements. Therefore, the new RDA were based on results from vitamin
E depletion studies carried out in humans in the 1950s. It is hoped
that further exploration of the function of -tocopherol will lead to
better estimations of human -tocopherol requirements for the
prevention of chronic diseases.
|
FOOTNOTES |
|---|
|
REFERENCES |
|---|
|
TOPABSTRACTINTRODUCTIONREFERENCES |
|---|
1.
Boscoboinik D., Szewczyk A., Hensey C., Azzi A. Inhibition of cell proliferation by -tocopherol. Role of protein kinase. C. J. Biol. Chem. 1991;266:6188-6194
2.
Cachia O., Benna J. E., Pedruzzi E., Descomps B., Gougerot-Pocidalo M. A., Leger C. L. -Tocopherol inhibits the respiratory burst in human monocytes.
Attenuation of p47(phox) membrane translocation and phosphorylation. J. Biol. Chem. 1998;273:32801-32805
3.
Chan A. C., Leith M. K. Decreased prostacyclin synthesis in vitamin E-deficient rabbit aorta. Am. J. Clin. Nutr. 1981;34:2341-2347
4. Chan A. C., Wagner M., Kennedy C., Chen E., Lanuville O., Mezl V. A., Tran K., Choy P. C. Vitamin E up-regulates arachidonic acid release and phospholipase A2 in megakaryocytes. Mol. Cell. Biochem. 1998a;189:153-159[Medline]
5. Chan A. C., Wagner M., Kennedy C., Mroske C., Proulx P., Laneuville O., Tran K., Choy P. C. Vitamin E up-regulates phospholipase A2, arachidonic acid release and cyclooxygenasein endothelial cells. Akt. Ernahr-Med. 1998b;23:1-8
6. Chatelain E., Boscoboinik D. O., Bartoli G.-M., Kagan V. E., Gey F., Packer L., Azzi A. Inhibition of smooth muscle cell proliferation and protein kinase C activity by tocopherols and tocotrienols. Biochim. Biophys. Acta 1993;1176:83-89[Medline]
7.
Clement S., Tasinato A., Boscoboinik D., Azzi A. The effect of -tocopherol on the synthesis, phosphorylation and activity of protein kinase C in smooth muscle cells after phorbol12-myristate 13-acetate down-regulation. Eur. J. Biochem. 1997;246:745-749[Medline]
8. Cominacini L., Garbin U., Pasini A. F., Davoli A., Campagnola M., Contessi G. B., Pastorino A. M., Lo Cascio V. Antioxidants inhibit the expression of intercellular cell adhesion molecule-1 and vascular adhesion molecule-1 induced by oxidized LDL on human umbilical vein endothelial cells. Free Radic. Biol. Med. 1997;22:117-127[Medline]
9.
Devaraj S., Adams-Huet B., Fuller C. J., Jialal I. Dose-response comparison of RRR--tocopherol and all-racemic -tocopherol on LDL oxidation. Arterioscler. Thromb. Vasc. Biol. 1997;17:2273-2279
10.
Devaraj S., Jialal I. -Tocopherol decreases interleukin-1ß release from activated human monocytes by inhibition of 5-lipoxygenase. Arterioscler. Thromb. Vasc. Biol. 1999;19:1125-1133
11. Devaraj S., Li D., Jialal I. The effects of alpha tocopherol supplementation on monocyte function. Decreased lipid oxidation interleukin 1 beta secretion, and monocyte adhesion to endothelium. J. Clin. Investig. 1996;98:756-763[Medline]
12.
Faruqi R., de la Motte C., DiCorleto P. E. -Tocopherol inhibits agonist-induced monocytic cell adhesion to cultured human endothelial cells. J. Clin. Investig. 1994;94:592-600
13.
Freedman J. E., Farhat J. H., Loscalzo J., Keaney J.F.J. -Tocopherol inhibits aggregation of human platelets by a protein kinase C-dependent mechanism. Circulation 1996;94:2434-2440
14.
Fuller C. J., Chandalia M., Garg A., Grundy S. M., Jialal I. RRR--Tocopheryl acetate supplementation at pharmacologic doses decreases low-density-lipoprotein oxidative susceptibility but not protein glycation in patients with diabetes mellitus. Am. J. Clin. Nutr. 1996;63:753-759
15. GISSI-Prevenzione Investigators Dietary supplementation with n-3 polyunsaturated fatty acids and vitamin E after myocardial infarction: results of the GISSI-Prevenzione trial. Lancet 1999;354:447-455[Medline]
16. Higashi O., Kikuchi Y. Effects of vitamin E on the aggregation and the lipid peroxidation of platelets exposed to hydrogen peroxide. Tohoku J. Exp. Med. 1974;112:271-278[Medline]
17.
Ishizuka T., Itaya S., Wada H., Ishizawa M., Kimura M., Kajita K., Kanoh Y., Miura A., Muto N., Yasuda K. Differential effect of the antidiabetic thiazolidinediones troglitazone and pioglitazone on human platelet aggregation mechanism. Diabetes 1998;47:1494-1500
18.
Islam K. N., Devaraj S., Jialal I. -Tocopherol enrichment of monocytes decreases agonist-induced adhesion to human endothelial cells. Circulation 1998;98:2255-2261
19.
Jialal I., Fuller C. J., Huet B. A. The effect of -tocopherol supplementation on LDL oxidation. A dose-response study. Arterioscler. Thromb. Vasc. Biol. 1995;15:190-198
20.
Keaney J.F.J., Simon D. I., Freedman J. E. Vitamin E and vascular homeostasis: implications for atherosclerosis. FASEB J 1999;13:965-975
21.
Martin A., Foxall T., Blumberg J. B., Meydani M. Vitamin E inhibits low-density lipoprotein-induced adhesion of monocytes to human aortic endothelial cells in vitro. Arterioscler. Thromb. Vasc. Biol. 1997;17:429-436
22. Molenaar R., Visser W. J., Verkerk A., Koster J. F., Jongkind J. F. Peroxidative stress and in vitro ageing of endothelial cells increases the monocyte-endothelial cell adherence in a human in vitro system. Atherosclerosis 1989;76:193-202[Medline]
23. National Research Council Dietary Reference Intakes for Vitamin C, Vitamin E, Selenium, and Carotenoids 2000 National Academy Press Washington, DC.
24. Pratico D., Tangirala R. K., Rader D. J., Rokach J., FitzGerald G. A. Vitamin E suppresses isoprostane generation in vivo and reduces atherosclerosis in apoE-deficient mice. Nat. Med. 1998;4:1189-1192[Medline]
25.
Rimm E. B., Stampfer M. J., Ascherio A., Giovannucci E., Colditz G. A., Willett W. C. Vitamin E consumption and the risk of coronary heart disease in men. N. Engl. J. Med. 1993;328:1450-1456
26.
Rota S., McWilliam N. A., Baglin T. P., Byrne C. D. Atherogenic lipoproteins support assembly of the prothrombinase complex and thrombin generation: modulation by oxidation and vitamin E. Blood 1998;91:508-515
27.
Stampfer M. J., Hennekens C., Manson J. E., Colditz G. A., Rosner B., Willett W. C. Vitamin E consumption and risk of coronary disease in women. N. Engl. J. Med. 1993;328:1444-1449
28.
Stauble B., Boscoboinik D., Tasinato A., Azzi A. Modulation of activator protein-1 (AP-1) transcription factor and protein kinase C by hydrogen peroxide and d--tocopherol in vascular smooth muscle cells. Eur. J. Biochem. 1994;226:393-402[Medline]
29. Steinberg, D. (1997) Oxidative modification of LDL and atherogenesis. The 1995 Lewis A. Conner Memorial Lecture. Circulation 95: 1062–1071.
30. Steiner M., Anastasi J. Vitamin E. An inhibitor of the platelet release reaction. J Clin Invest 1976;57:732-737
31. Stephens N. G., Parsons A., Schofield P. M., Kelly F., Cheeseman K., Mitchinson M. J. Randomised controlled trial of vitamin E in patients with coronary disease: Cambridge Heart Antioxidant Study (CHAOS). Lancet 1996;347:781-786[Medline]
32. Szczeklik A., Gryglewski R. J., Domagala B., Dworski R., Basista M. Dietary supplementation with vitamin E in hyperlipoproteinemias: effects on plasma lipid peroxides, antioxidant activity, prostacyclin generation and platelet aggregability. Thromb. Haemostasis 1985;54:425-430[Medline]
33.
Tasinato A., Boscoboinik D., Bartoli G., Maroni P., Azzi A. d--Tocopherol inhibition of vascular smooth muscle cell proliferation occurs at physiological concentrations, correlates with protein kinase C inhibition, and is independent of its antioxidant properties. Proc. Natl. Acad. Sci. U.S.A. 1995;92:12190-12194
34.
Terasawa Y., Ladha Z., Leonard S., Morrow J., Newland D., Sanan D., Packer L., Traber M. G., Farese R. V., Jr Increased atherosclerosis in hyperlipidemic mice deficient in -tocopherol transfer protein and vitamin E. Proc. Natl. Acad. Sci. U.S.A. 2000;97:13830-13834
35.
Thorin E., Hamilton C. A., Dominiczak M. H., Reid J. L. Chronic exposure of cultured bovine endothelial cells to oxidized LDL abolishes prostacyclin release. Arterioscler. Thromb. 1994;14:453-459
36.
Tran K., Chan A. R,R,R--Tocopherol potentiates prostacyclin release in human endothelial cells. Evidence for structural specificity of the tocopherol molecule. Biochim. Biophys. Acta 1990;1043:189-197
37. Tran K., Wong J. T., Lee E., Chan A. C., Choy P. C. Vitamin E potentiates arachidonate release and phospholipase A2 activity in rat heart myoblastic cells. Biochem. J. 1996;319:385-391
38.
Upston J. M., Terentis A. C., Stocker R. Tocopherol-mediated peroxidation of lipoproteins: implications for vitamin E as a potential antiatherogenic supplement. FASEB J 1999;13:977-994
39.
Yusuf S., Dagenais G., Pogue J., Bosch J., Sleight P. Vitamin E supplementation and cardiovascular events in high-risk patients. The Heart Outcomes Prevention Evaluation Study Investigators. N. Engl. J. Med. 2000;342:154-160
This article has been cited by other articles:
|
|
 |
|
  T. O Scholl, X. Chen, M. Sims, and T P. Stein Vitamin E: maternal concentrations are associated with fetal growth Am. J. Clinical Nutrition, December 1, 2006; 84(6): 1442 - 1448. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. C. McCormick and R. S. Parker The Cytotoxicity of Vitamin E Is Both Vitamer- and Cell-Specific and Involves a Selectable Trait J. Nutr., December 1, 2004; 134(12): 3335 - 3342. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. L Booth, I. Golly, J. M Sacheck, R. Roubenoff, G. E Dallal, K. Hamada, and J. B Blumberg Effect of vitamin E supplementation on vitamin K status in adults with normal coagulation status Am. J. Clinical Nutrition, July 1, 2004; 80(1): 143 - 148. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. C. Schwenke, L. L. Rudel, M. G. Sorci-Thomas, and M. J. Thomas {alpha}-Tocopherol protects against diet induced atherosclerosis in New Zealand white rabbits J. Lipid Res., November 1, 2002; 43(11): 1927 - 1938. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. A. Qureshi, W. A. Salser, R. Parmar, and E. E. Emeson Novel Tocotrienols of Rice Bran Inhibit Atherosclerotic Lesions in C57BL/6 ApoE-Deficient Mice J. Nutr., October 1, 2001; 131(10): 2606 - 2618. [Abstract] [Full Text] [PDF]
|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
