HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Kaul, N. Articles by Jialal, I. Search for Related Content PubMed PubMed Citation Articles by Kaul, N. Articles by Jialal, I.

---

MINIREVIEW

-Tocopherol and Atherosclerosis

Nalini Kaul^*, Sridevi Devaraj^* and Ishwarlal Jialal^*,,1

^* Departments of Pathology and
Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas 75390–9073

	Abstract

Top Abstract Introduction Oxidative Stress and... {alpha}-Tocopherol AT and Antioxidant Function AT-Molecular and Cellular... References

 
Cardiovascular disease is the leading cause of morbidity and mortality in the Western world. There is compelling evidence incriminating oxidative stress in the pathogenesis of the atherosclerotic lesion. Several lines of evidence suggest that antioxidants, especially -tocopherol, have potential beneficial effects with regard to cardiovascular disease. In vitro, -tocopherol has been shown to inhibit platelet adhesion and aggregation and smooth muscle cell proliferation, exert anti-inflammatory effects on monocytes, and improve endothelial function. Also, supplementation with -tocopherol has been shown to decrease lipid peroxidation, platelet aggregation, and pro-inflammatory activity of monocytes. However, clinical trials with -tocopherol supplementation to date have been equivocal. Thus, although mounting in vitro evidence and animal models provide a sound scientific basis for -tocopherol supplementation, further clinical trials are required before a definitive recommendation can be made with respect to the primary and secondary prevention of heart disease.

Key Words: -tocopherol • antioxidant • atherosclerosis • oxidative stress • inflammation

	Introduction

Top Abstract Introduction Oxidative Stress and... {alpha}-Tocopherol AT and Antioxidant Function AT-Molecular and Cellular... References

 
Atherosclerosis is the leading cause of death in the Western world. Considerable evidence suggests that oxidative stress and inflammation are central to atherogenesis. Epidemiologic studies suggest an association between increased antioxidant intake, especially vitamin E, and reduced morbidity and mortality from coronary artery disease. In this review, we will discuss the current literature with respect to -tocopherol and cardiovascular disease and the potential mechanisms involved.

	Oxidative Stress and Atherosclerosis

Top Abstract Introduction Oxidative Stress and... {alpha}-Tocopherol AT and Antioxidant Function AT-Molecular and Cellular... References

 
Clinical and epidemiological studies show that increased levels of low-density lipoprotein (LDL) cholesterol promote premature atherosclerosis. According to the oxidative modification hypothesis, the most plausible and biologically relevant modification of LDL is oxidation. LDL can be oxidatively modified by all major cells of the arterial wall (1, 2). In the early phase, mild oxidation of LDL results in the formation of minimally modified LDL (MM-LDL) in the subendothelial space. MM-LDL stimulates production of monocyte chemotactic protein-1 (MCP-1) that promotes monocyte chemotaxis. These molecular events result in monocyte binding to the endothelium and its subsequent migration into the subendothelial space where MM-LDL also stimulates production of monocyte colony stimulating factor (M-CSF). M-CSF promotes the differentiation of monocytes into macrophages. The macrophages can then further oxidize MM-LDL to Ox-LDL, which is not recognized by the LDL receptor but taken up avidly by the scavenger receptor pathway leading to appreciable cholesterol ester accumulation and foam cell formation.

Oxidized LDL has several biological consequences (1, 3); it promotes vasoconstriction, promotes adhesion, stimulates cytokines such as interleukin-1 (IL-1), increases platelet aggregation, inhibits nitric oxide tissue factor secretion, and stimulates plasminogen activator inhibitor-1 synthesis. Several lines of evidence support the in vivo existence of oxidized LDL (4–7): (i) antibodies against epitopes on Ox-LDL recognize material from atherosclerotic lesions, but not normal arteries; (ii) LDL extracted from lesions resembles LDL oxidatively modified in vitro; (iii) the presence of autoantibodies to Ox-LDL has been positively correlated to the progression of atherosclerosis, as manifested by carotid artery stenosis (8); and (iv) plasma concentrations of immunoreactive oxidized LDL are higher in patients with unstable angina, carotid atherosclerosis, and acute myocardial infarction than in normal subjects (9). However, the most persuasive evidence comes from animal studies in which antioxidant supplementation decreases lesion formation.

Recent direct evidence for the role of oxidative stress in atherosclerosis comes from studies with apoE-/-mice, which are good models of oxidative stress and spontaneously develop atherosclerosis similar to that found in humans. F₂-isoprostanes (10–13), considered direct measures of oxidative stress, have been found to localize in foam cells in atherosclerotic lesions and are significantly increased in the tissue, plasma, and urine of apoE knockout mice (12, 13).

Inflammation and Atherosclerosis.
A growing body of evidence implicates inflammatory reactions playing a major role in the development of atherosclerosis, thus, clearly supporting atherosclerosis as an inflammatory disease (2, 14). Major cellular participants in atherosclerosis include monocytes, macrophages, active vascular endothelium, T lymphocytes, platelets, and smooth muscle cells.

Monocytes and macrophages are critical cells present at all stages of atherogenesis and, when stimulated, can produce biologically active mediators that have a profound influence on the progression of atherosclerosis. Monocytes promote the peroxidation of lipids such as LDL through the generation of reactive oxygen species. Monocytes and macrophages secrete several proinflammatory, pro-atherogenic cytokines, such as IL-1 and TNF-, which have been shown to be present in the atherosclerotic lesion and are known to augment monocyte-endothelial adhesion. Although IL-1 has been shown to stimulate procoagulant activity, promote cholesterol esterification in macrophages, and stimulate smooth muscle proliferation via platelet-derived growth factor, TNF- has been shown to contribute to necrotic core by promoting apoptosis of macrophages and smooth muscle cells (15–17). Macrophages also release tissue factor, the major initiator of the blood coagulation cascade (15).

Atherosclerosis is associated with impaired endothelial cell (EC) function, and these changes attract and activate transendothelial migration of monocytes (18). Both IL-1 and TNF- stimulate expression of adhesion molecules, such as vascular cell adhesion molecule-1 (VCAM-1), intercellular cell adhesion molecule-1 (ICAM-1), and E-selectin (19, 20). Several studies have shown a strong association between levels of soluble CAMs and coronary as well as carotid atherosclerosis (21–24).

Many stimuli in response to inflammation, growth, and chemotactic factors from neighboring endothelial cells, monocytes, macrophages, and platelets induce smooth muscle cell (SMC) migration and subsequent proliferation, thereby resulting in narrowing of the lumen (20). SMC proliferation represents a significant central event in the fibrous plaque formation. The earliest event following plaque fissure is the adhesion and aggregation of platelets leading to thrombus formation. Increased platelet aggregation contributes to the development of atherosclerosis and increases the risk of myocardial infarction (MI). The inflammatory response of atherosclerosis is mediated by specific subtypes of T lymphocytes at every stage. Thus, there is a complex interaction of a wide variety of cells, and their activation leads to release of hydrolytic enzymes, cytokines, chemokines, and growth factors that can result in further injury.

	-Tocopherol

Top Abstract Introduction Oxidative Stress and... {alpha}-Tocopherol AT and Antioxidant Function AT-Molecular and Cellular... References

 
Dietary micronutrients with antioxidant properties may play an important role in the prevention of atherosclerosis. Vitamin E is the collective name for molecules that exhibit the biological activity of -tocopherol. Both naturally occurring and synthetic forms of vitamin E are present. Naturally occurring forms of vitamin E include four tocopherols and four tocotrienols (, ,, and ). Tocotrienols differ from tocopherol in that they have an unsaturated side chain and are potent cholesterol-lowering agents and antioxidants in animal bioassay systems; however, only -tocotrienol has been shown to possess antioxidant activity, and the purified tocotrienols, in a single human study, do not affect cholesterol levels (25). Synthetic vitamin E consists of eight sterioisomers. Since Trolox is a synthetic water-soluble tocopherol analog, and in humans lipid-soluble AT is carried in lipoprotein and delivered to tissues, studies with Trolox should be interpreted with caution.

-Tocopherol (AT), a chain-breaking antioxidant that traps peroxyl free radicals, is the principal and most potent lipid-soluble antioxidant in plasma and LDL. AT has proven to be effective in preventing lipid peroxidation and other radical-driven oxidative events (26). Several lines of evidence support a relationship between low AT levels and the development of atherosclerosis (27–30).

Animal Studies.
Though the earliest animal experiments yielded equivocal results with AT, most of the later studies have supported slow progression and prevention of atherosclerosis with AT. Verlangieri et al. (31) reported 35% inhibition of atherosclerotic lesion formation in cholesterol-fed macaques with AT supplementation as assessed by carotid Doppler studies over a 3-year period, whereas in another study of cholesterol-fed rabbits, Prasad et al. (32) reported 70% inhibition of atherosclerotic lesion formation with 40 mg/kg/day AT. Reduced restenosis after angioplasty in rabbits with established experimental atherosclerosis was seen following AT supplementation (33). In this study after 3 weeks following angioplasty, minimum luminal diameter was seen to decrease and the cross-sectional area of the intima-media was greater in the untreated group than in the group receiving AT 19 days before angioplasty (P < 0.001). In another study (34), dietary AT brought about a hypocholesterolemic response and conferred on LDL significant protection against oxidative modification in modified Watanabe rabbits. Either or both of these factors contributed to the inhibition of early aortic lesion development. In addition, Pratico et al. (35) reported that apoE knockout mice had increased atherogenesis and increased F₂-isoprostanes in urine, plasma, and vascular tissue; supplementation with AT (2000 IU/kg chow) significantly reduced isoprostanes generation and also aortic lesion but had no effect on plasma cholesterol levels. This is indicative of apoE-deficient mice having increased oxidative stress, which can be suppressed by AT. Also, chickens fed high doses of AT had reduced concentrations of plasma peroxides and less aortic intimal thickening compared with controls (36). The most persuasive data in animal models, of atherosclerosis showing a significant decrease in the degree of LDL oxidation and the extent of atherosclerotic lesions, comes from studies with antioxidants like AT, probucol, N,N-diphenyl phenylenediamine (DPPD), and butylated hydroxytoluene (BHT). However, the side effects of probucol and the toxicity of DPPD and BHT limit their use (37). Thus, the focus has been on AT.

Epidemiological Studies.
In 1991 the MONICA study, a cross-sectional study of 16 European populations, showed a significant correlation between AT concentrations and mortality in coronary artery disease (P < 0.002) (38). Three large prospective, epidemiologic studies that included the Nurses Health Study, which investigated 87,245 nurses, the Health Professionals Follow-Up Study, which investigated 39,910 male health professionals, and an older U.S. population study composed of 11,178 elderly individuals all found that AT supplementation reduced the risk of coronary artery disease. Both the Nurses and the Health Professionals studies found that subjects in the highest quintile of AT intake had about 40% reduction in cardiovascular disease (CVD) (28, 39). In the elderly, AT supplement use was associated with a 41% reduction in coronary artery disease (CAD) mortality and a 37% reduction in total mortality (30). Recently Kushi (40) reported a risk reduction of coronary mortality in 21,809 women from food-derived AT intake (>9.64 IU/day) and not from supplements. However, the number of women on supplements was small. Two other studies lend support to these earlier observations. One longitudinal study involving 5133 Finnish men and women reported an inverse association between dietary AT intake and coronary mortality (32% risk reduction) (41). A Canadian study of 2226 men also reported a significant risk reduction for subjects using AT (42). Retrospective evaluation of clinical trials like the Cholesterol-Lowering Atherosclerosis Study (CLAS), a randomized placebo–controlled study, provided additional support that coronary artery lesion progression was lowered with AT >100 IU/day (43). Azen (44) studying the progression of carotid atherosclerosis using ultrasound showed an effect in the placebo group opposite from results obtained in the coronary arteries by Hodis et al. (43) in the same CLAS study.

Intervention Studies.
The ATBC trial was the first double-blind randomized intervention trial in which AT (50 mg/day) and -carotene (20 mg/d) alone and in combination were given to reduce the incidence of lung cancer in a high-risk group of male smokers in Finland. Although AT had no effect on the primary end point (lung cancer), AT supplementation significantly reduced cerebral infarction and onset of angina but increased the risk of subarachnoid hemorrhages (45, 46). Further, AT supplementation (400 or 800 IU/day) compared with placebo, was shown to reduce nonfatal myocardial infarction by 77% in 2002 patients with angiographically proven coronary artery disease in the Cambridge Heart Antioxidant Study (CHAOS) (47). Also, Steiner et al. (48) have shown in a double-blind randomized study in 100 patients with transient ischemic attacks, that the group receiving AT (400 IU/day) in addition to aspirin had significantly decreased platelet adhesion and lower incidence of recurrent transient ischemic attacks and ischemic strokes than patients receiving aspirin alone. In a placebo controlled trial (49) DeMaio showed a decrease in restenosis rate with 1200 IU/day of AT (P < 0.06). Another Japanese study over a period of 6 years showed no abnormalities in ECG (P < 0.02) in the high AT intake group (50). Furthermore, the GISSI trial showed that in 2830 patients who had prior myocardial infarction and were on a Mediterranean diet (which is enriched with antioxidants), supplementation with all rac-AT (272 IU/day for 3.5 years) resulted in the following significant effects when the more appropriate 4-way analysis was undertaken: 20% reduction in cardiovascular deaths, 23% reduction in cardiac death, 25% reduction in coronary death, 35% reduction in sudden death despite the primary end point not being statistically significant (51). The Heart Outcomes Prevention Evaluation (HOPE) Study was recently published in which 2545 women and 6696 women 55 years or older who were at high risk for CAD events since they had CAD or diabetes in addition to one other risk factor were enrolled and randomized to receive 400 IU of AT from natural sources or placebo and either an angiotension converting enzyme (ACE) inhibitor or matching placebo for a mean of 4.5 years (52). Primary outcome was a composite of myocardial infarction, stroke, and CAD death. There were no significant differences in primary or secondary outcome variables in the subjects taking AT. However, this study was undertaken in many countries; dietary intakes especially of antioxidants were not reported, and no objective measures of supplementation (e.g., plasma levels of AT).

Although large cohort studies widely support the role of AT as an antioxidant against the proatherogenic and prothombotic effects of LDL oxidation, controlled trials on the other hand produced variable results. It is important to note that in CHAOS, GISSI, or HOPE that used higher doses of AT than in the ATBC trial, there was no increase in hemorrhagic strokes.

	AT and Antioxidant Function

Top Abstract Introduction Oxidative Stress and... {alpha}-Tocopherol AT and Antioxidant Function AT-Molecular and Cellular... References

 
Oxidation.
Several groups have also shown that - tocopherol inhibits LDL oxidation initiated by copper in vitro (53, 54) or by cells in culture (55). Esterbauer et al. (56) have shown that increasing LDL AT in vitro can prolong the lag phase of oxidation. Human studies have demonstrated that AT supplementation can reduce the susceptibility of LDL to oxidation (56–58). The minimum dose of AT required to obtain a beneficial effect on LDL was found to be 400 IU/day (56, 58).

AT may have additional benefits for cardiovascular disease. -Tocopherol supplementation may slow the progression of atherosclerosis by reducing oxidative stress, thereby decreasing lipid peroxidation and LDL oxidative susceptibility. In human subjects AT supplementation (100–600 mg/day for 2 weeks) has been shown to lower urinary F₂-isoprostanes by 34%–36% in hypercholesterolemic subjects and in diabetic individuals (59, 60). Also, in a recent report, our group has shown that supplementation of healthy adults with 400 IU/day RRR--tocopherol for 8 weeks resulted in lower levels of urinary F₂-isoprostanes (61).

	AT-Molecular and Cellular Effects

Top Abstract Introduction Oxidative Stress and... {alpha}-Tocopherol AT and Antioxidant Function AT-Molecular and Cellular... References

 
AT has antiatherogenic effects on cells crucial in atherogenesis (62) as outlined below.

AT and EC.
Adhesion of monocytes to the endothelium stimulates the expression of endothelium-derived adhesion molecules like endothelial leukocyte adhesion molecule (ELAM), ICAM-1 and VCAM-1, which aid in monocyte adhesion and their subsequent migration into the intima where monocytes differentiate into macrophages (9). Faruqi et al. (63) observed that when endothelial cells were cultured in the media containing AT, there was less agonist-induced adhesion of monocytes to EC which correlated with a decrease in message and cell surface expression of E-selectin. Cominacini et al. (64) have shown that pretreatment of endothelial cells (HUVEC) with AT significantly reduced the expression of the adhesion molecules ICAM-1 and VCAM-1 on HUVEC induced by oxidized LDL. Martin et al. (65) showed that in vitro enrichment of human aortic endothelial cells with AT significantly inhibited LDL-induced adhesion of monocytes to EC in a dose-dependent manner with a concomitant reduction in levels of ICAM.

A mechanism that may link inflammation and oxidative stress in atherosclerosis is the transcription factor NF- B, which is directly involved in the activation of genes responsible for inflammation. The importance of activated NF-B in atherosclerosis has been demonstrated in smooth muscle cells, macrophages, and endothelial cells of human atherosclerotic lesion tissue, but not in normal vessels (66, 67). A variety of genes included in atherosclerotic lesion, are regulated by NF-B, such as genes coding for ICAM-1 and VCAM-1 and cytokines. Schreck et al. (68) have suggested a novel signal transduction pathway for NF-B ctivation involving reactive oxygen species as second messengers, thus linking oxidative stress, inflammation, and atherosclerosis. Data from our laboratory has shown that pretreatment of monocytic cells with AT resulted in a decrease in monocyte-endothelial cell adhesion mediated by decreased expression of CD11b and VLA-4, possibly by inhibiting the activation of NF-B (69). -Tocopherol acetate and succinate have also been shown to inhibit TNF-–induced NF-B activation in-vitro (70). Thus AT has been shown to have beneficial effects in inhibiting monocyte-endothelial adhesion when incubated with either EC or monocytes, and it is very likely that following supplementation it partitions into both monocytes and EC, and its ability to reduce monocyte-EC adhesion is greater.

In atherosclerosis Ox-LDL accumulates in the vascular wall where it is cytotoxic and chemotactic for monocytes, leading to the production of oxygen-derived free radicals that can inactivate endothelium-derived nitric oxide. Keaney et al. (71) and Stewart-Lee et al. (72) showed that AT supplementation preserved endothelium-dependent vasorelaxation in cholesterol-fed rabbits by a mechanism independent of its effect on serum lipoproteins, and this did not correlate with lipoprotein oxidation. Furthermore, Keaney et al. (73) showed that AT incorporation in the artery wall prevents endothelial dysfunction caused by Ox-LDL, and this effect is mediated independent of its antioxidant effect. AT supplementation at high doses has been shown to preserve endothelium-dependent vasorelaxation in hypercholesterolemic men and smokers (74, 75). Arterial compliance or elasticity is a potential index of arterial function that has been shown to be dependent upon endothelial function (76). Although structural changes play a role in increased arterial stiffening, the functional component has been shown to be reversible with dietary interventions. Short-term AT supplementation (400 IU/day for 4 and 8 weeks) has been recently reported to improve arterial compliance in middle-aged men and women (77).

AT and Platelets.
AT modulates platelet adhesion and aggregation. Higashi and Kikuchi (78) were the first to demonstrate the inhibitory effect of AT on platelet aggregation in vitro. The effectiveness of AT as an anti aggregatory agent in vitro stands in contrast to its in vivo effect. Also Steiner (79) have shown that AT in doses 200 IU/day decreases platelet adhesion. In hypercholesterolemic subjects, 2 weeks of supplementation with AT (600 mg/day) reduced elevated plasma concentrations of the platelet-derived adhesion molecule, P-selectin by 40% (80). Furthermore, Steiner (81) have shown that at doses of 1200 IU/day, AT produced only a mild inhibition of collagen-induced platelet aggregation whereas platelet adhesion to collagen was markedly inhibited in its presence. Also, in another study, the same authors showed that in 100 patients with transient ischemic attacks, there was a significant reduction in platelet adhesion in patients given 400 IU/day of AT (50). A double-blind, randomized, placebo-controlled study was performed on 40 healthy volunteers (20–50 years) supplemented daily with vitamin E (300 mg), vitamin C (250 mg), or -carotene (15 mg) for 8 weeks (82). Platelet function was significantly decreased by vitamin E as revealed by the decreased platelet aggregation in response to ADP and arachidonic acid, the increased sensitivity to inhibition by PGE₁, the decreased plasma -thromboglobulin concentration and the decreased ATP secretion (82). Freedman et al. (83) have shown that supplementation with 400 IU of AT inhibits platelet aggregation through a PKC-dependent mechanism. In a recently published study, Mabile et al. (84) showed that the AT uptake by platelets is optimal at 75 IU/day, and this correlates with the maximal influence on platelet aggregation and platelet responsiveness to inhibition by PGE₁. Increased supplemental levels (200, 400 IU/day) failed to exert greater effects.

AT and Monocytes/Macrophages.
AT has been shown to inhibit macrophage-mediated lipid oxidation in vitro. However, there is limited data on the effect of AT on monocyte function. Our group has shown that supplementation with 1200 IU/day of AT significantly influenced monocyte function by decreasing lipid oxidation, release of O₂^– and hydrogen peroxide, decreasing release of the pro-atherogenic cytokine, IL-1, as well as decreasing monocyte-endothelial cell adhesion. (1200 IU/day significantly reduced superoxide anion release by 45%, hydrogen peroxide release by 40%, lipid oxidation by 40%, release of IL-1 by 90% as well as monocyte-endothelial cell adhesion by 35% (85). Also, we have recently shown that monocytes from type II diabetic subjects with and without macrovascular disease are more pro-atherogenic than matched controls as assessed by increased levels of superoxide and interleukin-1 and greater adhesion to endothelium. AT supplementation (1200 IU/day) significantly reduced monocyte-proatherogenic activity. In addition, AT supplementation also resulted in a significant inhibition of levels of soluble adhesion molecules, ICAM, VCAM and E-selectin (86).

One common mechanism to account for AT's effects may be through protein kinase C (PKC) inhibition (87). PKC plays a major role in signal transduction and has been implicated in a variety of events ranging from respiratory burst and platelet aggregation to cellular differentiation. Many oxidant-initiated signaling processes are known to involve PKC. It has been shown previously that O₂^– release and lipid oxidation are mediated via PKC (88). Our group has shown that AT decreases monocyte superoxide anion release and lipid oxidation, and this appears to be mediated by inhibition of protein kinase C. Furthermore, results from an in vitro study by Cachia et al. (89) revealed that AT inhibits superoxide production by monocytes by impairing the assembly of NADPH oxidase, the enzyme responsible for generating the respiratory burst. AT inhibits p47phox translocation to the membrane and also impairs phosphorylation of p47phox. This study also suggests that inhibition of PKC activity is not due directly to the antioxidant capacity of AT, but requires AT integration into the cell membrane where it can interact directly with PKC.

With regard to cytokine release, we have shown that AT inhibits IL1 release from activated human monocytes by inhibiting 5-lipoxygenase at the post-transcriptional levels (90). Also, as discussed previously, we have shown that - tocopherol enrichment of monocytes inhibits subsequent adhesion to human endothelium via inhibition of counter receptors, CD11 and VLA-4 on the monocytes and inhibition of the transcription factor, NF-B (69).

Also, AT has recently been demonstrated to downregulate scavenger activity (SR) activity in human blood–derived macrophages in vitro, whereas -tocopherol, a homolog of AT, showed only a weak suppression of SR activity, SR- class A expression, and AP-1 activity (91).

T and SMC.
AT has been reported to inhibit SMC proliferation in culture. The antiproliferative effects of AT have been well demonstrated in rat aortic SMC stimulated with platelet derived growth factor (PDGF) (92–96), and the effect has not been related to its antioxidant effect (92–96). These studies collectively suggest that AT inhibits SMC proliferation in vivo and thus retards narrowing of the artery lumen. The role of AT in cellular signaling especially in relation to PKC has been delineated by Azzi et al. (87). They have shown that this effect is not related to ATs antioxidant effects because only RRR--tocopherol, and not -tocopherol, binds to a receptor resulting in activation of AP-1 leading to the dephosphorylation of PKC even though both have similar antioxidant activity. In fact -tocopherol has been reported to actually abrogate the -tocopherol effect. Thus RRR-AT appears to act as a sensor of the oxidation status of the cell and as a transducer capable of informing cells of the oxidation status. There is compelling data suggesting that antioxidant activity alone cannot mediate PKC inhibition (92–96). Direct inhibition of PKC by AT does not appear likely as several studies showed no effect on diacylglycerol or calcium-stimulated PKC and -2 activity (97–100). An indirect mechanism for AT inhibition of PKC seems more likely and data to support this come from smooth muscle cells where PKC 2 is activated by hyperglycemia and AT inhibits this effect by decreasing cellular DAG levels (97–100) through stimulation of DAG kinase activity. Also it has been demonstrated that okadaic acid prevents the antiproliferative effect of AT in SMC proliferation clearly indicating that PKC phosphorylation and/or protein phosphatase activity is involved. Evidence for AT inhibition of SMC proliferation is mostly in vitro, and there are few data available in vivo. De Maio et al. (49) reported a trend in patients following percutaneous transluminal coronary angioplasty (PTCA) supplemented with 1200 IU/day for 4 months, indicating that AT supplementation reduces the incidence of coronary artery restenosis after angioplasty. The ability of AT to reduce restenosis after angioplasty was further tested in a rabbit model in which angioplasty was performed on established atherosclerotic lesions (33). Ox-LDL stimulated DNA synthesis in rabbit vascular smooth muscle cells, and AT was found to inhibit this effect. These findings support the hypothesis that oxidized lipids can stimulate hyperplasia, and AT limits this effect by inhibiting either oxidation or the proliferative effects of oxidants on cells.

Thus, in addition to AT being a potent antioxidant as evidenced by decreased LDL oxidative susceptibility and F₂-isoprostanes, it has additional biological effects such as inhibition of platelet aggregation, decreasing monocyte pro-atherogenic activity, and improving endothelial function.

It is clear that AT demonstrates a multifaceted effect promoting vascular homeostasis. In vivo supplementation with AT has clearly shown that it is an antioxidant that inhibits platelet aggregation and is anti-inflammatory (Table I). Though we are beginning to unravel the molecular mechanisms by which AT acts, precise mechanistic understanding still eludes us. The epidemiological evidence from studies with AT, though strong, needs to be confirmed by clinical trials before treatment strategies can be formulated for both primary and secondary prevention.

View this table: [in this window] [in a new window]   Table I. Effects of -Tocopherol Supplementation

	Footnotes

 
Funding was provided by NIH RO1 AT00005–02 and NIH K24 AT00596–01.

¹ To whom requests for reprints should be addressed at the Division of Clinical Biochemistry and Human Metabolism, The University of Texas Southwestern Medical Center at Dallas, Dallas, TX 753909073. E-mail: jialal.i{at}pathology.swmed.edu

	References

Top Abstract Introduction Oxidative Stress and... {alpha}-Tocopherol AT and Antioxidant Function AT-Molecular and Cellular... References

 

1. Berliner JA, Navab M, Fogelman AM, Frank JS, Demer LL, Edwards PA, Watson AD, Lusis AJ. Atherosclerosis: Basic mechanisms, oxidation, inflammation, and genetics. Circulation 91:2488–2496, 1995.[Abstract/Free Full Text]
2. Ross R. Atherosclerosis: An inflammatory disease. N Engl J Med 340:115–126, 1999.[Free Full Text]
3. Jialal I, Grundy SM. Influence of antioxidant vitamins on LDL oxidation. Ann N Y Acad Sci 669:237–248, 1992.[Medline]
4. Steinberg D, Parthasarathy S, Carew T, Khoo JC, Witztum JL. Beyond cholesterol: Modifications of low-density lipoprotein that increase its atherogenicity. N Engl J Med 320:915–924, 1989.[Medline]
5. Steinbrecher U, Zhang H, Lougheed M. Role of oxidatively modified LDL in atherosclerosis. Free Radic Biol Med 9:155–168, 1990.[Medline]
6. Witztum J, Steinberg D. Role of oxidized low-density lipoprotein in atherogenesis. J Clin Invest 88:1785–1792, 1991.
7. Jialal I, Grundy S. Effect of dietary supplementation with -tocopherol on the oxidative modification of low-density lipoprotein. J Lipid Res 33:899–906, 1992.[Abstract]
8. Salonen JT, Yla-Herttuala S, Yamamoto R, Butler S, Korpela H, Salonen R, Nyyssonen K, Palinski W, Witztum JL. Autoantibody against oxidized LDL and progression of carotid atherosclerosis. Lancet 339:883–887, 1992.[Medline]
9. Holvoet P, Collen D. Oxidized lipoproteins in atherosclerosis and thrombosis. FASEB J 8:1279–1284, 1994.[Abstract]
10. Roberts L II, Morrow J. The generation and actions of isoprostanes. Biochim Biophys Acta 1345:121–135, 1997.[Medline]
11. Patrano C, FitzGerald G. Isoprostanes: Potential markers of oxidant stress in atherothrombotic disease. Arterioscler Thromb Vasc Biol 17:2309–2315, 1997.[Abstract/Free Full Text]
12. Pratico D, Iuliano L, Mauriello A, Spagnoli L, Lawson JA, Rokach J, Maclouf J, Violi F, FitzGerald GA. Localization of distinct F₂-isoprostanes in human atherosclerotic lesions. J Clin Invest 100:915–924, 1997.
13. Gniwotta C, Morrow JD, Roberts LJ II, Kuhn H. Prostaglandin F₂-like compounds, F₂-isoprostanes, are present in increased amounts in human atherosclerotic lesions. Arterioscler Thromb Vasc Biol 17:3236–3241, 1997.[Abstract/Free Full Text]
14. Libby P. Molecular basis of the acute coronary syndromes. Circulation 91:2844–2850, 1995.[Free Full Text]
15. Libby P, Hanson G. Biology of disease: Involvement of the immune system in atherogenesis: Current knowledge and unanswered questions. Lab Invest 64:5–13, 1991.[Medline]
16. Rus H, Niculescu Z, Vlaicu R. TNF- in human arterial wall with atherosclerosis. Atherosclerosis 89:247–254, 1991.[Medline]
17. Mantovani A, Sozzani S, Introna M. Endothelial activation by cytokines. Ann N Y Acad Sci 832:93–116, 1997.[Free Full Text]
18. Hennig B, Toborek M, Joshi-Barve S, Barger SW, Barve S, Mattson MP, McClain CJ. Linoleic acid activates NF-B and induces NF-B–dependent transcription in cultured endothelial cells. Am J Clin Nutr 63:322–328, 1996.[Abstract/Free Full Text]
19. Clinton S, Libby P. Cytokines and growth factors in atherogenesis. Arch Pathol Lab Med 116:1292–1300, 1992.[Medline]
20. Raines E, Ross R. Multiple growth factors are associated with lesions of atherosclerosis: Specificity or redundancy? Bioessays 18:271–282, 1996.[Medline]
21. Hwang SJ, Ballantyne CM, Sharrett AR, Smith LC, Davis CE, Gotto AM Jr., Boerwinkle E. Circulating adhesion molecules VCAM-1, ICAM-1, and E-selectin in carotid atherosclerosis and incident coronary heart disease cases (ARIC). Circulation 96:4219–4225, 1997.[Abstract/Free Full Text]
22. De Caterina R, Basta G, Lazzerini G, DelOmo G, Petrucci R, Morale M, Carmassi F, Pedrinelli R. Soluble VCAM-1 as a biohumoral correlate of atherosclerosis. Arterioscler Thromb Vasc Biol 17:2646–2654, 1997.[Abstract/Free Full Text]
23. Rohde LE, Lee RT, Rivero J, Jamacochian M, Arroyo LH, Briggs W, Rifai N, Libby P, Creager MA, Ridker PM. Circulating cell adhesion molecules are correlated with ultrasound-based assessment of carotid atherosclerosis. Arterioscler Thromb Vasc Biol 18:1765–1770, 1998.[Abstract/Free Full Text]
24. Ridker PH, Roitman J. Plasma concentration of soluble ICAM-1-1 and risks of future MI in apparently healthy men. Lancet 351:88–92, 1998.[Medline]
25. O'Byrne D, Grundy S, Packer L, Devaraj S, Baldenius K, Hoppe P, Kramer K, Jialal I, Traber MG. Studies of LDL oxidation following -, -, or -tocotrienyl acetate supplementation in hypercholesterolemic humans. Free Radic Biol Med, 2000, in press.
26. Devaraj S, Jialal I. Oxidized LDL and atherosclerosis. Int J Clin Lab Res 26:178–184, 1996.[Medline]
27. Riemersma RA, Wood DA, Macintyre CC, Elton RA, Gey KF, Oliver MF. Risk of angina pectoris and plasma concentrations of vitamins A, C, and E and carotene. Lancet 337:1–5, 1991.[Medline]
28. Rimm EB, Stampfer MJ, Ascherio A, Giovannucci E, Colditz GA, Willett WC. Vitamin E consumption and the risk of coronary heart disease in men. N Engl J Med 328:1450–1456, 1993.[Abstract/Free Full Text]
29. Gey K, Puska P, Jordan P, Moser U. Inverse correlation between vitamin E and mortality from ischemic heart disease in cross-cultural epidemiology. Am J Clin Nutr 53:326–331, 1992.
30. Losonczy K. Vitamin E and vitamin C supplement use and risk of all cause and coronary heart disease mortality in older persons: The established populations for epidemiologic studies of the elderly. Am J Clin Nutr 64:190–196, 1996.[Abstract/Free Full Text]
31. Verlangieri A, Buxh M. Effects of --tocopherol supplementation on experimentally induced primate atherosclerosis. J Am Coll Nutr 11:131–138, 1992.[Abstract]
32. Prasad J. Effect of vitamin E supplementation on leukocyte function. Am J Clin Nutr 33:606–608, 1980.[Abstract/Free Full Text]
33. Lafont AM, Chai YC, Cornhill JF, Whitlow PL, Howe PH, Chisolm GM. Effect of -tocopherol on restenosis after angioplasty in a model of experimental atherosclerosis. J Clin Invest 95:1018–1025, 1995.
34. Williams RJ, Motteram JM, Sharp CH, Gallagher PJ. Dietary vitamin E and attenuation of early lesion development in modified Watanabe rabbits. Atherosclerosis 94:153–159, 1992.[Medline]
35. Pratico D, Tangirala RK, Rader DJ, Rokach J, FitzGerald GA. Vitamin E suppresses isoprostane generation in vivo and reduces atherosclerosis in apoE-deficient mice. Nat Med 4:1189–1192, 1998.[Medline]
36. Smith T, Kummerow F. Effect of dietary vitamin E on plasma lipids and atherogenesis in restricted ovulator chicken. Atherosclerosis 75:105–109, 1989.[Medline]
37. Devaraj S, Jialal I. Oxidized low density lipoprotein and artheriosclerosis. Int J Clin Lab Res 26:178–184, 1996.
38. Gey K, Puska P, Jordan P, Moser UK. Inverse correlation between plasma vitamin E and mortality from ischemic heart disease in cross-cultural epidemiology. Am J Clin Nutr 53(Suppl):326S–334S, 1991.[Abstract/Free Full Text]
39. Stampfer MJ, Hennekens CH, Manson JE, Colditz GA, Rosner B, Willett WC. A prospective study of vitamin E supplementation and risk of coronary disease in women. N Engl J Med 328:1444–1449, 1993.[Abstract/Free Full Text]
40. Kushi LH, Folsom AR, Prineas RJ, Mink PJ, Wu Y, Bostick RM. Dietary antioxidant vitamins and death from coronary heart disease in postmenopausal women. New Engl J Med 334:1156–1162, 1996.[Abstract/Free Full Text]
41. Knekt P, Reunanen A, Jarvinen R, Seppanen R, Heliovaara M, Aromaa A. Antioxidant vitamin intake and coronary mortality in a longitudinal population study. Am J Epidemiol 139:1180–1189, 1994.[Abstract/Free Full Text]
42. Meyer F, Bairati I, Dagenais G. Lower ischemic heart disease (IHD) incidence and mortality among vitamin supplement users in a cohort of 2226 men. 2nd International Conference. Antioxidant Vitamins and -Carotene in Disease Prevention. Berlin, 1994.
43. Hodis HN, Mack WJ, LaBree L, Cashin-Hemphill L, Sevanian A, Johnson R, Azen SP. Serial coronary angiographic evidence that antioxidant vitamin intake reduces progression of coronary artery atherosclerosis. JAMA 273:1849–1854, 1995.[Abstract]
44. Azen SP, Qian D, Mack WJ, Sevanian A, Selzer RH, Liu CR, Liu CH, Hodis HN. Effect of supplementary antioxidant vitamin intake on carotid arterial wall IMT in a controlled clinical trial of cholesterol lowering. Circulation 94:2369–2372, 1996.[Abstract/Free Full Text]
45. Rapola J. Randomized trial of -tocopherol and -carotene supplements on incidence of major coronary events in men with previous myocardial infarction. Lancet 349:1715–1720, 1997.[Medline]
46. Knekt P. Serum vitamin E levels and risk of female cancer. Int J Epidemiol 17:281–285, 1988.[Abstract/Free Full Text]
47. Stephens NG, Parsons A, Schofield PM, Kelly F, Cheeseman K, Mitchinson MJ. Randomized controlled trial of vitamin E in patients with coronary disease: Cambridge Heart Antioxidant Study (CHAOS). Lancet 347:781–786, 1996.[Medline]
48. Steiner M, Glantz M, Lekos A. Vitamin E plus aspirin compared to aspirin alone in patients with TIA. Am J Clin Nutr 62:1381–1384, 1995.
49. DeMaio SJ, King SB III, Lembo NJ, Roubin GS, Hearn JA, Bhagavan HN, Sgoutas DS. Vitamin E supplementation, plasma lipids, and incidence of restenosis after percutaneous transluminal coronary angioplasty (TCA). J Am Coll Nutr 11:68–73, 1992.[Abstract]
50. Takamatsu S, Takamatsu M, Satoh K. Effects on health of dietary supplementation with 100 mg --tocopheryl acetate, daily for 6 years. J Int Med Res 23:342–357, 1995.[Medline]
51. Investigators G. Dietary supplementation with n-3PUFA and vitamin E after myocardial infarction: Results of the GISSI-Prevenzione trial. Lancet 354:447–455, 1999.[Medline]
52. The HOPE Investigators. Vitamin E supplementation and cardiovascular events in high risk patients: HOPE. N Engl J Med 342:154–161, 2000.[Abstract/Free Full Text]
53. Reaven P, Witztum J. Comparison of supplementation with RRR--tocopherol and allrac tocopherol in humans. Arterioscler Thromb Vasc Biol 13:601–608, 1993.[Abstract/Free Full Text]
54. Jialal I, Fuller C, Huet B. The effect of -tocopherol supplementation on LDL oxidation: A dose-response study. Arterioscler Thromb 15:190–198, 1995.[Abstract/Free Full Text]
55. Steinbrecher U. Modification of low-density lipoprotein by endothelial cells involves lipid peroxidation and degradation of low-density lipoprotein phospholipids. Proc Natl Acad Sci U S A 81:3883–3887, 1984.[Abstract/Free Full Text]
56. Esterbauer H, Dieber-Rotheneder M, Striegl G, Waeg G. Role of vitamin E in preventing the oxidation of low-density lipoprotein. Am J Clin Nutr 53(Suppl 1):314S–321S, 1991.[Abstract/Free Full Text]
57. Jialal I, Grundy S. Influence of antioxidant vitamins on LDL oxidation. Ann N Y Acad Sci 669:237–248, 1992.
58. Devaraj S, Adams-Huet B, Fuller CJ, Jialal I. Dose-response comparison of RRR-- tocopherol and all-rac -tocopherol on LDL oxidation. Arterioscler Thromb Vasc Biol 17:2273–2279, 1997.[Abstract/Free Full Text]
59. Davi G, Alessandrini P, Mezzetti A, Minotti G, Bucciarelli T, Costantini F, Cipollone F, Bon GB, Ciabattoni G, Patrono C. In vivo formation of 8-epi-prostaglandin-F₂ is increased in hypercholesterolemia. Arterioscler Thromb Vasc Biol 17:3230–3235, 1997.[Abstract/Free Full Text]
60. Davi G, Ciabattoni G, Consoli A, Mezzetti A, Falco A, Santarone S, Pennese E, Vitacolonna E, Bucciarelli T, Costantini F, Capani F, Patrono C. In vivo formation of 8-epi-PGF₂- and platelet activation in diabetes mellitus: Effect of improved metabolic control and vitamin E supplementation. Circulation 99:224–229, 1999.[Abstract/Free Full Text]
61. Marangon K, Devaraj S, Jialal I. The effect of -lipoate and -tocopherol on plasma, whole body, and LDL oxidation. Free Radic Biol Med 27:1114–1121, 1999.[Medline]
62. Devaraj S, Jialal I. The effects of -tocopherol on critical cells in atherogenesis. Curr Opin Lipidol 9:1115, 1998.
63. Faruqui R, De La Motte C, Dicorleto P. -Tocopherol inhibits agonist-induced monocyte cell adherence to cultured human endothelial cells. J Clin Invest 94:592–600, 1994.
64. Cominacini L, Garbin U, Pasini AF, Davoli A, Campagnola M, Contessi GB, Pastorino AM, Lo Cascio V. Antioxidants inhibit the expression of intercellular cell adhesion molecule-1 and vascular cell adhesion molecule-1 induced by oxidized LDL on human umbilical vein endothelial cells. Free Radic Biol Med 22:117–127, 1997.[Medline]
65. Martin A, Foxall T, Blumberg JB, Meydani M. AT inhibits LDL-induced adhesion of monocytes to human aortic endothelial cells in vitro. Arterioscler Thromb Vasc Biol 17:429–436, 1997.[Abstract/Free Full Text]
66. Brand K, Page S, Rogler G, Bartsch A, Brandl R, Knuechel R, Page M, Kaltschmidt C, Baeuerle PA, Neumeier D. Activated transcription factor NF-B is present in the atherosclerotic lesion. J Clin Invest 97:1715–1722, 1996.[Medline]
67. Collins T. Endothelial NF-B and the initiation of the atherosclerotic lesion. Lab Invest 68:499–506, 1993.[Medline]
68. Schreck R, Rieber P, Baeuerle P. Reactive oxygen intermediates as apparently widely used messengers in the activation of NF-B and HIV-1. EMBO J 10:2247–2258, 1991.[Medline]
69. Islam K, Devaraj S, Jialal I. -Tocopherol enrichment of monocytes decreases agonist-induced adhesion to human endothelial cells. Circulation 98:2255–2261, 1998.[Abstract/Free Full Text]
70. Suzuki Y, Packer L. Inhibition of NF-B DNA binding activity by AT succinate. Biochem Mol Biol Int 31:693–700, 1993.[Medline]
71. Keaney JF Jr., Gaziano JM, Xu A, Frei B, Curran-Celentano J, Shwaery GT, Loscalzo J, Vita JA. Low-dose -tocopherol improves and high-dose -tocopherol worsens endothelial vasodilator function in cholesterol-fed rabbits. Clin Invest 93:844–851, 1994.
72. Stewart-Lee AL, Forster LA, Nourooz-Zadeh J, Ferns GA, Anggard EE. Vitamin E protects against impairment of endothelium-mediated relaxations in cholesterol-fed rabbits. Arterioscler Thromb Vasc Biol 14:494–499, 1994.[Abstract/Free Full Text]
73. Keaney JF Jr., Guo Y, Cunningham D, Shwaery GT, Xu A, Vita JA. Vascular incorporation of -tocopherol prevents endothelial dysfunction due to oxidized LDL by inhibiting protein kinase C stimulation. J Clin Invest 98:386–394, 1996.[Medline]
74. Heitzer T, Yia Herttualla S, Wild E, Luoma J, Drexter H. Effect of vitamin E on endothelial vasodilator function in patients with hypercholesterolemia, chronic smoking, or both. J Am Coll Cardiol 33:499–505, 1999.[Abstract/Free Full Text]
75. Motoyama T, Kawano H, Kugiyama K, Hirashima O, Ohgushi M, Tsunoda R, Moriyama Y, Miyao Y, Yoshimura M, Ogawa H, Yasue H. Vitamin E administration improves impairment of endothelium-dependent vasodilation in patients with coronary spastic angina. J Am Coll Cardiol 32:1672–1679, 1998.[Abstract/Free Full Text]
76. Ramsey MW, Goodfellow J, Jones CJ, Luddington LA, Lewis MJ, Henderson AH. Endothelial control of arterial distensibility is impaired in chronic heart failure. Circulation 92:3212–3219, 1995.[Abstract/Free Full Text]
77. Mottrram P, Shige H, Nestel P. Vitamin E improves arterial compliance in middle-aged men and women. Atherosclerosis 145:399–404, 1999.[Medline]
78. Higashi O, Kikuchi Y. Effects of vitamin E on the aggregation and lipid peroxidation of platelets exposed to hydrogen peroxide. Tohoku J Exp Med 112:271–278, 1974.[Medline]
79. Steiner M. Influence of vitamin E on platelet function in humans. J Am Coll Nutr 10:466, 1991.[Abstract]
80. Davi G, Romano M, Mezzetti A, Procopio A, Iacobelli S, Antidormi T, Bucciarelli T, Alessandrini P, Cuccurullo F, Bittolo Bon G. Increased levels of soluble P-selectin in hypercholesterolemic patients. Circulation 97:953–957, 1998.[Abstract/Free Full Text]
81. Steiner M. Effect of alpha tocopherol administration on platelet function in man. Thromb Haemostasis 49:73–77, 1983.[Medline]
82. Calzada C, Bruckdorfer K, Rice Evans C. The influence of antioxidant nutrients on platelet function in healthy volunteers. Atherosclerosis 128:97–105, 1997.[Medline]
83. Freedman JE, Farhat JH, Loscalzo J, Keaney JF Jr. -Tocopherol inhibits aggregation of human platelets by a protein kinase C– dependent mechanism. Circulation 94:2434–2440, 1996.[Abstract/Free Full Text]
84. Mabile L, Bruckdorfer K, Rice Evans C. Moderate supplementation with natural -tocopherol decreases platelet aggregation and low-density lipoprotein oxidation. Atherosclerosis 147:177–185, 1999.[Medline]
85. Devaraj S, Li D, Jialal I. The effect of -tocopherol supplementation on monocyte function: Decreased lipid oxidation, interleukin-1 secretion, and monocyte adhesion to endothelium. J Clin Invest 98:756–763, 1996.[Medline]
86. Devaraj S, Jialal I. Low-density lipoprotein postsecretory modification, monocyte function, and circulating adhesion molecules in type II diabetic patients with and without macrovascular complications: The effect of -tocopherol supplementation. Circulation 102:191–196, 2000.[Abstract/Free Full Text]
87. Azzi A, Aratri E, Boscoboinik D, Clement S, Ozer NK, Ricciarelli R, Spycher S. Molecular basis of -tocopherol control of smooth muscle cell proliferation. Biofactors 7:314, 1998.
88. Li Q, Cathcart M. Protein kinase C activity is required for lipid oxidation of low-density lipoprotein by activated human monocytes. J Biol Chem 269:17508–17515, 1994.[Abstract/Free Full Text]
89. Cachia O, Benna JE, Pedruzzi E, Descomps B, Gougerot-Pocidalo MA, Leger CL. -Tocopherol inhibits the respiratory burst in human monocytes: Attenuation of p47 (phox) membrane translocation and phosphorylation. J Biol Chem 273:32801–32805, 1998.[Abstract/Free Full Text]
90. Devaraj S, Jialal I. -Tocopherol inhibits IL- release by inhibition of 5-lipoxygenase. Arterioscler Thromb Vasc Biol 19:1125–1133, 1999.[Abstract/Free Full Text]
91. Teupser D, Thiery J, Seidel D. -Tocopherol downregulates scavenger receptor activity in macrophages. Atherosclerosis 144:109–115, 1999.[Medline]
92. Boscoboinik D, Szewczyk A, Hensey C, Azzi A. Inhibition of cell proliferation by -tocopherol, role of PKC. J Biol Chem 266:6188–6194, 1991.[Abstract/Free Full Text]
93. Azzi A, Boscoboinik D, Marilley D, Ozer NK, Stauble B, Tasinato A. Vitamin E: A sensor and an information transducer of the cell oxidation state. Am J Clin Nutr 62 (Suppl):1337S–1364S, 1995.[Abstract/Free Full Text]
94. Chatelain E, Boscoboinik DO, Bartoli GM, Kagan VE, Gey FK, Packer L, Azzi A. Inhibition of smooth muscle cell proliferation and protein kinase C activity by tocopherols and tocotrienols. Biochim Biophys Acta 1176:83–89, 1993.[Medline]
95. Ozer N, Boscoboinik D, Azzi A. New roles of low-density lipoproteins and vitamin E in the pathogenesis of atherosclerosis. Biochem Mol Biol Int 35:117–124, 1995.[Medline]
96. Tasinato A, Boscoboinik D, Bartoli GM, Maroni P, Azzi A. --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 92:12190–12194, 1995.[Abstract/Free Full Text]
97. Kunisaki M, Bursell SE, Umeda F, Nawata H, King GL. Normalization of DAG-PKC activation by vitamin E in aorta of diabetic rats and cultured rat SMC exposed to elevated glucose levels. Diabetes 42:1372–1377, 1994.[Abstract]
98. Kunisaki M, Bursell SE, Clermont AC, Ishii H, Ballas LM, Jirousek MR, Umeda F, Nawata H, King GL. Vitamin E prevents diabetes-induced abnormal retinal flow via the diacylglycerol protein kinase C pathway. Am J Physiol 269:E239–E246, 1995.[Abstract/Free Full Text]
99. Koya D, Haneda M, Kikkawa R, King GL. --Tocopherol treatment prevents glomerular dysfunctions in diabetic rats through inhibition of protein-kinase C–diacylglycerol pathway. Biofactors 7:69–76, 1998.[Medline]
100. Keaney JF, Simon D, Freedman J. Vitamin E and vascular homeostasis: Implications for atherosclerosis. FASEB J 13:965–976, 1999.[Abstract/Free Full Text]

This article has been cited by other articles:

				A. R. Judge, J. T. Selsby, and S. L. Dodd Antioxidants attenuate oxidative damage in rat skeletal muscle during mild ischaemia Exp Physiol, April 1, 2008; 93(4): 479 - 485. [Abstract] [Full Text] [PDF]

				I. Sundl, M. Guardiola, G. Khoschsorur, R. Sola, J. C. Vallve, G. Godas, L. Masana, M. Maritschnegg, A. Meinitzer, N. Cardinault, et al. Increased concentrations of circulating vitamin E in carriers of the apolipoprotein A5 gene 1131T>C variant and associations with plasma lipids and lipid peroxidation J. Lipid Res., November 1, 2007; 48(11): 2506 - 2513. [Abstract] [Full Text] [PDF]

				D. Wu, L. Liu, M. Meydani, and S. N. Meydani Vitamin E Increases Production of Vasodilator Prostanoids in Human Aortic Endothelial Cells through Opposing Effects on Cyclooxygenase-2 and Phospholipase A2 J. Nutr., August 1, 2005; 135(8): 1847 - 1853. [Abstract] [Full Text] [PDF]

				I. Jialal and S. Devaraj Scientific Evidence to Support a Vitamin E and Heart Disease Health Claim: Research Needs J. Nutr., February 1, 2005; 135(2): 348 - 353. [Abstract] [Full Text] [PDF]

				S. Devaraj and M. G Traber {gamma}-Tocopherol, the new vitamin E? Am. J. Clinical Nutrition, March 1, 2003; 77(3): 530 - 531. [Full Text] [PDF]

				I. Jialal and S. Devaraj Antioxidants and Atherosclerosis: Don't Throw Out the Baby With the Bath Water Circulation, February 25, 2003; 107(7): 926 - 928. [Full Text] [PDF]

				R. M. Salonen, K. Nyyssonen, J. Kaikkonen, E. Porkkala-Sarataho, S. Voutilainen, T. H. Rissanen, T.-P. Tuomainen, V.-P. Valkonen, U. Ristonmaa, H.-M. Lakka, et al. Six-Year Effect of Combined Vitamin C and E Supplementation on Atherosclerotic Progression: The Antioxidant Supplementation in Atherosclerosis Prevention (ASAP) Study Circulation, February 25, 2003; 107(7): 947 - 953. [Abstract] [Full Text] [PDF]

				S. Devaraj, A. V. C. Chan Jr., and I. Jialal {alpha}-Tocopherol Supplementation Decreases Plasminogen Activator Inhibitor-1 and P-Selectin Levels in Type 2 Diabetic Patients Diabetes Care, March 1, 2002; 25(3): 524 - 529. [Abstract] [Full Text] [PDF]

This Article Abstract Full Text (PDF) Alert me when this article is cited