Cellular, molecular and clinical aspects of vitamin E on atherosclerosis prevention

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Molecular Aspects of Medicine 28 (2007) 538–590 www.elsevier.com/locate/mam

Review

Cellular, molecular and clinical aspects of vitamin E on atherosclerosis prevention Adelina Munteanu a, Jean-Marc Zingg a

b,*

Physiology Department, Faculty of Medicine, University of Medicine and Pharmacy Bucharest, Romania b Institute of Biochemistry and Molecular Medicine, University of Bern, Bu¨hlstrasse 28, 3012 Bern, Switzerland Received 23 July 2007; accepted 23 July 2007

Abstract Randomised clinical trials and epidemiologic studies addressing the preventive effects of vitamin E supplementation against cardiovascular disease reported both positive and negative effects, and recent meta-analyses of the clinical studies were rather disappointing. In contrast to that, many animal studies clearly show a preventive action of vitamin E in several experimental settings, which can be explained by the molecular and cellular effects of vitamin E observed in cell cultures. This review is focusing on the molecular effects of vitamin E on the cells playing a role during atherosclerosis, in particular on the endothelial cells, vascular smooth muscle cells, monocytes/macrophages, T cells, and mast cells. Vitamin E may act by normalizing aberrant signal transduction and gene expression in antioxidant and non-antioxidant manners; in particular, over-expression of scavenger receptors and consequent foam cell formation can be prevented by vitamin E. In addition to that, the cellular effects of a-tocopheryl phosphate and of

Abbreviations: CAD, coronary artery disease; CVD, cardiovascular disease; ERa, estrogen receptor alpha; HDL, high density lipoproteins; IMT, intima-media-thickness; LDL, low density lipoproteins; MI, myocardial infarction; oxLDL, oxidized low density lipoproteins; PKC, protein kinase C; PMA, phorbol 12myristate 13-acetate; ROS, reactive oxygen species; RNS, reactive nitrogen species; a-TTP, a-tocopherol transfer protein; a-TOS, a-tocopheryl succinate; a-TEA, a-tocopheryl oxyacetic acid; VLDL, very low density lipoproteins. * Corresponding author. Tel.: +41 31 631 41 18; fax: +41 31 631 37 37. E-mail address: [email protected] (J.-M. Zingg). 0098-2997/$ - see front matter  2007 Elsevier Ltd. All rights reserved. doi:10.1016/j.mam.2007.07.001

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EPC-K1, a composite molecule between a-tocopheryl phosphate and L-ascorbic acid, are summarized.  2007 Elsevier Ltd. All rights reserved. Keywords: Vitamin E; Tocopherol; Tocotrienol; Tocopheryl phosphate; EPC-K1; Atherosclerosis; Epidemiological studies; Animal studies; Endothelial cells; Monocytes; Macrophages; T cells; Mast cells; Vascular smooth muscle cells; Scavenger receptors; Gene expression; Signal transduction

Contents 1. 2. 3.

4.

5.

6.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Atherosclerosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Clinical and animal studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1. Clinical studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1.1. Epidemiologic studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1.2. Randomised clinical trials . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1.3. Antioxidant combination supplementation studies . . . . . . . . . . . . 3.1.4. Meta-analyses. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2. Animal studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.3. Arterial imaging studies in humans and animals. . . . . . . . . . . . . . . . . . . Modulation of the vascular system cells involved in atherosclerosis by vitamin E . . 4.1. Modulation of endothelial cells by vitamin E. . . . . . . . . . . . . . . . . . . . . 4.1.1. Vitamin E prevents apoptosis and increases the survival of endothelial cells . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.1.2. Vitamin E modulates adhesion molecules expression on endothelial cells . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.1.3. Vitamin E modulates angiogenesis by endothelial cells . . . . . . . . . 4.1.4. Vitamin E modulates endothelial-derived nitric oxide production . 4.2. Modulation of vascular smooth muscle cells by vitamin E . . . . . . . . . . . 4.3. Modulation of monocytes, macrophages and T cells by vitamin E . . . . . . 4.4. Modulation of mast cells by vitamin E . . . . . . . . . . . . . . . . . . . . . . . . . Modulation of signal transduction and gene expression by vitamin E in cells of the vascular system . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.1. Scavenger receptors are induced by various stimuli. . . . . . . . . . . . . . . . . 5.2. Inhibition of scavenger receptor expression by vitamin E and prevention of atherosclerosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.3. Over-expression of scavenger receptor CD36 by ritonavir is prevented by vitamin E . . . . . . . . . . . . . . . . . . . . . . . . . 5.4. Molecular and cellular effects of a-tocopheryl phosphate and EPC-K1 in cells of the vascular system . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conclusions. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

539 540 541 541 541 543 545 546 548 549 551 551 552 552 554 554 555 559 562 563 563 565 566 567 568 569

1. Introduction Increased plasma cholesterol levels and oxidative stress are known to enhance the risk for cardiovascular diseases. Based on this, current strategies to prevent

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atherosclerosis are aimed either at lowering the cholesterol load of lipoproteins or at reducing oxidative stress, e.g. by supplementation with molecules able to scavenge free radicals, such as vitamins E and C. Several studies have described preventive effects of vitamin E (a-tocopherol) supplementation against atherosclerosis, but a secure correlation is not universally accepted (reviewed in Brigelius-Flohe et al., 2005; Munteanu et al., 2004b; Zingg and Azzi, 2004). Vitamin E present in circulating lipoproteins (mainly LDL) and in the subendothelial space has been hypothesized to play a central role in reducing atherosclerosis by preventing the formation of oxidized small molecules, proteins, and lipids, which may induce cellular de-regulation and consequent lesion development (Upston et al., 2003). In addition to its potential antioxidant effects, vitamin E can exert non-antioxidant activities suggesting alternative molecular pathways for disease prevention, e.g. by direct interaction with structural proteins, membranes, enzymes, and transcription factors in cells of the vascular system, such as endothelial cells, vascular smooth muscle cells, monocytes/macrophages, T cells, and mastocytes (Brigelius-Flohe et al., 2002; Ricciarelli et al., 2001; Rimbach et al., 2002; Zingg and Azzi, 2004).

2. Atherosclerosis Atherosclerosis, a chronic inflammatory disease initiated by monocyte/lymphocyte adhesion to activated endothelial cells, underlies important adverse vascular events such as coronary artery disease, stroke and peripheral artery disease, responsible for most of the cardiovascular morbidity and mortality today. A variety of factors contribute to the development and progression of atherosclerosis. Injury and dysfunction of the endothelium, which maintains vascular homeostasis by regulating vascular tonus, smooth muscle cell proliferation and thrombogenicity, is thought to be one of the earliest steps (Davignon and Ganz, 2004). Inflammation, macrophage infiltration, extracellular matrix proteolysis, oxidative stress, lipid deposition, cell apoptosis and thrombosis are among further molecular mechanisms contributing to plaque development and progression (Naghavi et al., 2003). The earliest visible atherosclerotic lesion is the fatty streak, which comprises an area of intimal thickening containing macrophages overloaded with lipid droplets (known as foam cells), lymphocytes and vascular smooth muscle cells (VSMC). Plaques develop as a result of the accumulation of modified low-density lipoproteins (LDL) in the subendothelial space mediated by over-expression of scavenger receptors (Sections 5.1 and 5.2), followed by the diapedesis of leukocytes and formation of foam cells, proliferation of VSMC and production of connective tissue. Plaque rupture and thrombus formation are the last stages of the atherosclerotic process, leading to clinical events involving coronary, cerebral and peripheral arteries (Libby, 2001). Until the beginning of the 20th century, the theories explaining the pathogenesis of atherosclerosis were purely descriptive, based on the anatomical observation of

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human atherosclerotic vessels. The work of Ignatovski, Anitschkov and Chalatov gave rise to the lipid theory of atherosclerosis that predominated for most of the 20th century, by reproducing experimental atherosclerosis in rabbits fed a hypercholesterolic diet (Anitschkow and Chalatov, 1913). Half a century later, Brown and Goldstein showed that the LDL receptor they had discovered, a cell surface protein that binds LDL and removes them from blood (Brown and Goldstein, 1986), is not involved in foam cell formation and proposed that a receptor recognizing acetylated LDL has the key role in this process (Goldstein et al., 1979). Steinberg and his group (Steinberg et al., 1989) demonstrated during the 1980s the central role of oxidized LDL (oxLDL) in the pathogenesis of atherosclerosis, and a number of scavenger receptors for these lipids were identified (reviewed in Libby and Li, 1993). At the beginning of the 1990s, apolipoprotein E- and LDL receptor-deficient mice, derived by homologous recombination techniques (Ishibashi et al., 1993, 1994b; Plump et al., 1992; Zhang et al., 1992) were shown to develop arterial lesions that progress from foam cell-rich fatty streaks to fibro-proliferative plaques with lipid/necrotic cores, similar to the evolution of human lesions (Ishibashi et al., 1994a; Nakashima et al., 1994; Reddick et al., 1994). With the possibility of abolishing the expression of a single gene of interest, or of over-expressing it in these atherosclerosis mouse models, a new era of atherosclerosis research at a mechanistic level was entered, which gave insight into the multiple causes of atherosclerosis as well as into the action of many preventive agents, including antioxidants and micronutrients (Tedgui and Mallat, 2006).

3. Clinical and animal studies 3.1. Clinical studies Based on a large body of experimental work, oxidative stress is thought to play a key role in the pathogenesis of atherosclerosis (Steinberg and Lewis, 1997). By extension, antioxidants may have a beneficial role in modulating oxidative damage and thus decreasing the risk of atherosclerosis lesion formation and progression. In spite of substantial experimental evidence demonstrating prevention of atherosclerosis in experimental settings, no clear benefits have been observed in large clinical trials in which antioxidants have been given to high-risk patients for the prevention of cardiovascular events (Minuz et al., 2006). Antioxidant vitamins C and E (L-ascorbic acid and a-tocopherol, respectively) are one of the main defence mechanisms of the body’s non-enzymatic antioxidant system, and the preventive effects of vitamin E assessed in clinical studies are reviewed in the following. 3.1.1. Epidemiologic studies Vitamin E has been the focus of several large supplementation studies of cardiovascular disease due to its effective antioxidant ability in lipid environments, including lipoproteins and cellular membranes. The initial enthusiasm for the clinical use of antioxidant vitamins in the prevention of cardiovascular disease stemmed from

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positive results in the preclinical setting. In particular, animal data suggested that vitamin E prevented initiation of disease progression in laboratory animals without known atherosclerosis (Parker et al., 1995; Prasad and Kalra, 1993). LDL isolated from subjects taking vitamin E supplements (P400 IU) is less susceptible to ex vivo oxidation (Devaraj et al., 1997; Fuller et al., 1996; Jialal et al., 1995). Such early positive findings and the presumed safety of antioxidant supplementation led to large, prospective cohort studies, in which an association between antioxidant vitamin intake, serum vitamin concentrations, or both, and improved cardiovascular outcomes have been reported. Men and women with vitamin E supplement intakes >100 IU/day for P2 years had a significant reduction of heart attacks (Losonczy et al., 1996; Rimm et al., 1993; Stampfer et al., 1993). A cross sectional study of sixteen European populations showed a significant correlation between a-tocopherol concentrations and mortality in coronary artery disease (MONICA) (Gey et al., 1991). Another study reported a risk reduction of coronary artery disease mortality in post-menopausal women with food-derived a-tocopherol intake and not from supplements; though, the number of women on supplements was small (Kushi et al., 1996). Similar results were reported by a longitudinal study on Finnish men and women (32% risk reduction) (Knekt et al., 1994) and by a Canadian study involving only men (Meyer et al., 1996). In a case control study enrolling 123 subjects with myocardial infarction (MI), males and females, a protective association with a-tocopherol supplementation was suggested only among persons with high plasma levels of serum cholesterol (Street et al., 1994). Retrospective evaluation of clinical trials like the CholesterolLowering Atherosclerosis Study (CLAS), a randomized placebo-controlled study, reported that coronary artery lesion progression was decreased with a-tocopherol >100 IU/day (Hodis et al., 1995). A case control study measuring lipid peroxidation products and vitamin E in 100 patients with coronary artery disease and in a matched control group, reported that total plasma a-tocopherol was similar in all groups, whereas the a-tocopherol content per LDL particle was lowest in patients with unstable angina pectoris, followed by patients with stable angina pectoris and then controls; lipid peroxidation products were increased in patients with unstable angina pectoris and discriminated stable angina pectoris (Kostner et al., 1997). Another study, enrolling 104 carotid endarterectomy patients investigated the effects of short-term a-tocopherol supplementation (500 IU/day) on lipid oxidation in plasma and in advanced atherosclerotic lesions (Carpenter et al., 2003). The inverse correlation between plaque a-tocopherol concentrations and cholesterol oxidation, the increased plasma LDL resistance to oxidation in vitamin E supplemented subjects, and the absence of significant elevation of cholesterol-standardized atocopherol mean concentration in established atherosclerotic plaques support the belief that antioxidant vitamins can protect against lipid oxidation in atherosclerosis (Meagher et al., 2001). However, in the EURAMIC study a-tocopherol and b-carotene had no protective effect (Kardinaal et al., 1993). Recently, the Physicians Health Study (PHS) reported a prospective nested case-control study of male physicians diagnosed with acute

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myocardial infarction, without prior history of cardiovascular disease, paired with control subjects and matched for age, smoking habit, and plasma levels of a- and c-tocopherol (Hak et al., 2003). Men with higher plasma levels of c-tocopherol tended to have increased risk of acute myocardial infarction; though, these findings were not confirmed in prospective cohort randomised trials. In the Multiple Risk Factor Intervention Trial (MRFIT), the blood levels of a- and c-tocopherol, carotenoids and retinol were not related to fatal or non-fatal myocardial infarction in males with history of nonfatal myocardial infarction or death from coronary artery disease (Evans et al., 1998). Another case-control study on 46 patients of fatal and non-fatal myocardial infarction, males and females, reported no difference in mean lipid adjusted serum vitamin E concentration between cases and controls (Hense et al., 1993). 3.1.2. Randomised clinical trials Prospective cohort randomised trials of antioxidant protection against cardiovascular disease have focused most attention on vitamin E, due to the encouraging results provided by epidemiological studies. Table 1 summarizes the data reported by the major clinical trials investigating the efficacy of vitamin E in preventing cardiovascular disease. The subjects enrolled in primary prevention studies had risk factors but no preexisting cardiovascular disease. The Finnish Alpha-Tocopherol Beta Carotene study (ATBC) (Rapola et al., 1996) reported a decrease of the incidence of angina pectoris, no effect of vitamin E supplementation on the cardiovascular mortality, and an increase of hemorrhagic strokes (but a decrease of cerebral infarction (Leppala et al., 2000)), compared to the control subjects. Although the ATBC used a low dose of synthetic vitamin E (50 mg/day), the median level of a-tocopherol increased significantly, from 28.8 lmol/l at base line to 42.5 mmol/l at three months. It is important to note that in randomized studies that used higher doses of a-tocopherol than in the ATBC trial (CHAOS, GISSI, or HOPE), there was no increase in hemorrhagic strokes (Kaul et al., 2001). The Collaborative Primary Prevention Project (PPP) (de Gaetano, 2001) showed no effect on the main combined endpoints (CVD death, MI, stroke), but the incidence of peripheral-artery disease was significantly lower among subjects treated with vitamin E (relative risk ratio of 46%). The Antioxidant Supplementation in Atherosclerosis Prevention (ASAP) study (Salonen et al., 2000) investigated the effect of RRR-a-tocopheryl-acetate, slowrelease vitamin C, a combination of both or placebo on the progression in intimato-media thickness (IMT) of common carotid artery, used as a marker of on-going atherosclerotic disease. Only the male smokers treated with both vitamins showed a relevant decrease in the rate of IMT progression. In the Vitamin E Atherosclerosis Prevention Study (VEAPS) vitamin E supplementation showed no effect on IMT progression in men and women with LDL cholesterol P3.37 mmol/l (Hodis et al., 2002). The secondary prevention trials were designed to investigate vitamin E supplementation in patients with clinical evidence of CVD (Table 1). In the Cambridge Heart Antioxidant Study (CHAOS) (Stephens et al., 1996), supplementation with vitamin E induced a major decrease in the risk of non-fatal acute MI, but there

544

Trial

Subjects

Vitamin E dose and type

Follow-up (years)

Parameters

Relative risk

Primary prevention ATBC Male smokers; 50–69 years PPP High risk for CVD; mean age 64.4 years

29,133 4495

50 mg all rac-tocopheryl-acetate 300 mg all rac-a-tocopherol

6.1 3.6

MI, stroke deaths CVD mortality, MI

0.95 0.87

ASAP

458

3.0

Peripheral-artery disease IMT progression

0.54 0.56

350

136 IU, 2·/day RRR-atocopheryl-acetate 400 IU/day DL-a-tocopherol

3.0

IMT progression

1.74

Secondary prevention CHAOS CAD patients; mean age 62 years

2002

400–800 IU RRR-a-tocopherol

1.4

SPACE

196

800 IU RRR-a-tocopherol

1.4

CVD and total mortality Non-fatal MI MI, CVD mortality

1.18 0.23 0.46

11,324

300 mg all rac-a-tocopherol

3.5

CVD mortality, non-fatal MI

0.88

9541

400 IU/day RRR-a-tocopherylacetate 400 IU/day RRR-a-tocopherylacetate

4.5

CVD mortality

1.05

4.0

IMT progression in common carotid artery

1

VEAPS

GISSI HOPE SECURE

History

Plasma cholesterol >5 mM; 45– 69 years Plasma cholesterol >3.4 mM; over 40 years old

Hemodialysis and known CVD; 40–75 years Recent MI (<3 months); 50–80 years CVD or diabetes patients; mean age 66 CVD and diabetes patients

732

CAD – coronary artery disease; CVD – cardiovascular disease; MI – myocardial infarction; IMT – intima-to-media thickness, see text for references.

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Table 1 Clinical trials of vitamin E supplementation effect on cardiovascular disease

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was no difference in CVD deaths. The mean a-tocopherol levels increased from 34.2 to 51.1 mmol/l in patients receiving 400 IU/day (which was the case for the majority of the subjects) and to 64.5 mmol/l in patients receiving 800 IU/day. The Secondary Prevention with Antioxidants of Cardiovascular Disease in Endstage Renal Disease (SPACE) study (Boaz et al., 2000) reported a significant reduction of the acute MI incidence in hemodialysed patients who received vitamin E. However, two other large prospective trials, the Gruppo Italiano per lo Studio della Supervienza nell’Infarto miocardico (GISSI) (Marchioli, 1999) and the Heart Outcomes Prevention Evaluation (HOPE) study (Yusuf et al., 2000), showed no effect of vitamin E treatment on any cardiovascular event. The HOPE study had high rates of compliance, involved high risk patients, and the large number of primary outcomes conferred a high statistical power. Though, 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 a-tocopherol) were provided (Kaul et al., 2001). A reevaluation of the data (Jialal et al., 1999; Ng et al., 1999; Salen and de Lorgeril, 1999) suggested more recently that cardiovascular mortality was significantly reduced by vitamin E in GISSI and the effect on overall survival showed a favorable trend. In a sub-study of the HOPE trial, the SECURE study, vitamin E realised no benefit on the rate of IMT progression in patients with cardiovascular disease or diabetes (Lonn et al., 2001). 3.1.3. Antioxidant combination supplementation studies Primary and secondary prevention studies have been designed for investigating the effects of vitamin E supplementation on cardiovascular disease in combination with other antioxidants. In the ASAP study, vitamin E and C administered together to hypercholesterolemic subjects decreased IMT progression in male, with a nonsignificant effect in female subjects (Salonen et al., 2000). The effect was larger in subjects with low baseline vitamin C or atherosclerotic plaques. In the Harvard IVUS trial, supplementation with vitamins E and C significantly inhibited the progression of coronary atherosclerosis in 1 year (reviewed in Salonen, 2002). These data confirming that the supplementation with a combination of vitamins E and C can reduce atherosclerotic progression were followed by trials reporting opposite results. In the WAVE study, progression of coronary artery disease in postmenopausal women with P15–75% stenosis worsened non-significantly with the combination of vitamin E and C compared to placebo (Waters et al., 2002). The combination of vitamin E with b-carotene in men with established cardiovascular disease showed no benefit on major coronary events (Rapola et al., 1996). In a secondary prevention trial, the Heart Protection Study (HPS) investigating the benefit of vitamins E, C and bcarotene, the blood antioxidant levels were increased substantially by supplementation, but no influence on the incidence of cardiovascular disease or other major outcomes was observed (Group HPC, 2002). The Supplementation en Vitamines et Mineraux Antioxydants (SU.VI.MAX) study, a randomized, double-blind, placebo-controlled primary prevention trial enrolling a total of 13,017 French adults that received a combination of vitamin

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C, E, b-carotene, selenium and zinc for 7.5 years, showed no effect on ischemic cardiovascular disease incidence or all-cause mortality, and no improvement on carotid atherosclerosis and arterial stiffness (Hercberg et al., 2004). The MRC/BCF Heart Protection Study Collaborative Group 2001, a randomized trial of cholesterol-lowering therapy and of antioxidant vitamins in people at increased risk of CAD death, has shown that statins can reduce the risk of heart attack or stroke by up to one third but vitamins C and/or vitamin E were without evident benefit (Group HPC, 2002). Moreover, the HDL Atherosclerosis Treatment Study (HATS) demonstrated a clinical benefit in coronary artery disease patients with low HDL cholesterol levels treated with simvastatin and niacin or simvastatin–niacin plus antioxidants (vitamin E, C, b-carotene and selenium) compared with antioxidants alone or placebo; angiographically documented stenosis regressed in the simvastatin–niacin group but progressed in the others (Matthan et al., 2003), suggesting that combined antioxidant vitamin therapy may diminish the benefits on coronary disease obtained with a statin and niacin (Brown et al., 2001). However, transplant associated atherosclerosis seems to be prevented by supplementation with combined vitamin E and C. In a double-blind prospective trial, 40 patients (0–2 years after cardiac transplantation) were randomly assigned vitamin C (500 mg) plus vitamin E (400 IU) or placebo (n = 21). After 1-year of treatment, the average intimal index increased in the placebo group but did not change significantly in the treatment group (0.8%; p = 0.008), and coronary endothelial function remained stable in both groups (Fang et al., 2002). Interestingly, although the antioxidant vitamins reduced disease progression in transplanted patients with normal or abnormal endothelial function, the magnitude of benefit was larger in patients with endothelial dysfunction (Behrendt et al., 2006). 3.1.4. Meta-analyses A number of meta-analyses of primary and secondary prevention trials were conducted to assess the effect of antioxidant vitamins on long term cardiovascular mortality and morbidity. The lack of a significant effect was persistently observed for various doses of vitamin E in diverse populations (Alkhenizan and Al-Omran, 2004; Bleys et al., 2006; Eidelman et al., 2004; Knekt et al., 2004; Pham and Plakogiannis, 2005; Shekelle et al., 2004; Vivekananthan et al., 2003). Nevertheless, one meta-analysis showed an association of vitamin E supplementation with a statistically significant reduction in non-fatal myocardial infarction in patients with pre-existing coronary artery disease (Alkhenizan and Al-Omran, 2004). Most of these studies reported vitamin E of not adversely affecting cardiovascular outcomes either. Though, a recent meta-analysis of 19 clinical trials concluded that the regular administration of high-dose vitamin E supplements (P400 IU/day) is associated with a small but statistically significant increase of mortality (Miller et al., 2005). A number of critical comments were addressed to Miller and colleagues’ metaanalysis regarding the statistical methods used, the lack of controlling for study quality and publication or selection bias (see Baggott, 2005; Blatt and Pryor, 2005; DeZee et al., 2005; Hemila, 2005; Jialal and Devaraj, 2005; Krishnan et al., 2005; Lim et al., 2005; Marras et al., 2005; Meydani et al., 2005b; Miller et al., 2005; Possolo, 2005).

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Another comprehensive review including 68 randomized primary and secondary prevention trials with almost a quarter of a million participants, assessed the effect of antioxidant supplements on mortality (Bjelakovic et al., 2007). Vitamin E given singly or combined with four other antioxidants did not significantly influence mortality, but after exclusion of high-bias risk trials, however, vitamin E given singly or in combination significantly increased mortality. A recent population based study, The Cache County Study (Hayden et al., 2007), investigated whether the mortality risk with vitamin E emphasized by Miller et al. reflect adverse consequences of its use in the presence of cardiovascular disease. The results showed no overall change in mortality with vitamin E use, but the null relationship seemed to represent a combination of increased mortality in those with severe cardiovascular disease and a possible protective effect in those without. The increased overall mortality in subjects with preexisting cardiovascular disease or diabetes seemed to relate in part to specific and harmful interactions between the use of vitamin E and either nitrates or warfarin. The adverse interaction of vitamin E with warfarin could be explained by its inhibitory effect on vitamin K-dependent clotting (Corrigan and Marcus, 1974; Olson, 1984), but the interaction with nitrates, especially evident in this study, is more difficult to be understood, although some hypothesis are available (Munzel et al., 1995; Thatcher et al., 2004; Watanabe et al., 1997). Thus, it would be useful to investigate further potential interactions between vitamin E and medications commonly used for cardiac illness. In a randomized, placebo-controlled trial of daily vitamin E supplementation in adults with asthma a 27% increase in plasma oxidation activity levels was observed in patients receiving vitamin E (Pearson et al., 2006). In line with this, experimental data suggest that vitamin E can become pro-oxidant and that combined antioxidant vitamins can reduce the HDL2-subfraction (Brown et al., 2001). Thus, another explanation of increased mortality observed in intervention studies using this nutrient may be the pro-oxidant effect of high-dose vitamin E supplementation. Previous meta-analysis, however, demonstrated that vitamin E supplements up to 800 mg/day for up to 6.5 years (Kraemer et al., 2004), or in amounts 61600 IU (1073 mg RRR-a-tocopherol or the molar equivalent of its esters) (Hathcock et al., 2005) are safe. Likewise, as safety guidance, the Food and Nutrition Board, Institute of Medicine, has established the tolerable upper intake levels for vitamin E at 1000 mg (Food and Nutrition Board IoM, 2000). High-dosage trials were often small and were performed in patients with chronic diseases. Therefore, the presumable damage caused by vitamin E administered in doses bigger than 400 IU/day is improbable in healthy subjects, and a precise threshold at which risk increases is difficult to be set. The relation between mortality and circulating concentrations of vitamin E resulting from dietary intake, low-dose supplementation, or both is yet insufficiently explored. In summary, the often neutral outcome of secondary prevention studies suggests that vitamin E supplementation is not an effective therapy against pre-existing cardiovascular disease, but rather may play a preventive role as evidenced in the more positive outcome seen in primary prevention and epidemiologic studies.

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3.2. Animal studies Although the earliest animal experiments yielded equivocal results, some of the later studies have supported slower progression and prevention of atherosclerosis by vitamin E supplementation. In cholesterol-fed rabbits, atherosclerotic lesion formation was reduced by 70% with a-tocopherol treatment (Prasad, 1980). Similar to that, in New Zealand white rabbits fed a high cholesterol diet, atherosclerotic lesions were decreased after a-tocopherol supplementation (Schwenke et al., 2002). In another study, dietary a-tocopherol supplementation of modified Watanabe rabbits reduced plasma cholesterol levels and significantly protected LDL against oxidative modification with consequent inhibition of early aortic lesion development (Williams et al., 1992). In hypercholesterolemic rabbits, atherosclerotic lesions and CD36 scavenger receptor over-expression were normalized by vitamin E treatment suggesting reduced foam cell formation. The novel tocopherol analogue, a-tocopheryl phosphate was more potent in preventing atherosclerosis progression in this animal model, when compared to a-tocopheryl acetate (Negis et al., 2006). In mice, the deletion of the ApoE gene (ApoE/) elevated the level of F2isoprostanes in urine, plasma, and vascular tissue and increased the formation of atherosclerotic lesions; a-tocopherol supplementation significantly reduced F2-isoprostanes generation and also aortic lesions but had no effect on plasma cholesterol levels in these mice (Pratico et al., 1998). Similar to that, a 60% decrease of the atherosclerotic lesions as a result of vitamin E supplementation and decreased monocyte chemoattractant protein-1 (MCP-1) expression was measured in ApoE/ knockout mice fed an atherogenic diet (Peluzio et al., 2001, 2003). It is interesting to note that several studies using animals fed a standard chow, which already contains higher amounts of a-tocopherol compared to the Western type diet, showed no clear beneficial effect on atherosclerosis development after extra vitamin E supplementation; this situation may in fact partially explain the often negative outcome of human clinical studies surveying patients without any documented impaired vitamin E transport or dietary deficiency (Robinson et al., 2006; Upston et al., 1999). Contrary to that, in studies using vitamin E deficient animals, a-tocopherol supplementation was clearly correlated with reduction of atherosclerosis. Severe atherosclerotic lesions in the proximal aorta developed in ApoE/ knockout mice that were crossed with a-TTP-deficient mice (a-TTP/) thus having decreased atocopherol levels in plasma and tissue (Terasawa et al., 2000), and vitamin E supplementation protected against atherosclerosis in these mice (Suarna et al., 2006). A significant decrease in LDL oxidation and in atherosclerotic lesion formation was shown in studies with antioxidants like a-tocopherol, probucol, N,N-diphenylphenylenediamine (DPPD), and butylated hydroxytoluene (BHT) (Devaraj and Jialal, 1996). In contrast to that, no increased levels of oxLDL were measured in a-TTP/ mice having severe vitamin E deficiency, but instead many alterations in the gene expression pattern were detected. Interestingly, no significant changes in the expression of enzymes dealing with scavenging reactive oxygen species (ROS) were seen (which are expected to be induced by oxidative stress), suggesting that in these experiments a-tocopherol may not primarily scavenge free radicals but plays

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alternative roles in the development of atherosclerosis (Barella et al., 2004; Gohil et al., 2003; Oommen et al., 2007). On the other hand, probucol strongly protected LDL from oxidation to oxLDL, but failed to decrease atherogenesis in LDLR/ mice, again suggesting alternative pathways of prevention. This is also supported by a recent study with hyperlipidemic mice, which showed prevention against atherosclerosis by vitamin E supplementation in situations of severe vitamin E deficiency (a-TTP/), and this effect was independent of preventing lipid oxidation in the vessel wall (Suarna et al., 2006). 3.3. Arterial imaging studies in humans and animals In vivo, the preventive effect of vitamin E on atherosclerosis is best reflected by measuring the intima-media-thickness of the artery (IMT). The extent of atherosclerosis at early, subclinical stages can be measured by high-resolution ultrasound measurements of the arterial wall thickness (Hodis et al., 1996; Selzer et al., 1994). Although IMT ultimately reflects VSMC proliferation, the effects seen with vitamin E can be explained by both a direct modulation of VSMC and by an indirect action on neighbouring cells. In the ARIC (Atherosclerosis Risk in Communities) study, the relationship between the intake of dietary and supplemental vitamin C, a-tocopherol, and provitamin A carotenoids and average carotid artery wall thickness was studied in 6318 female and 4989 male participants 45–64 years old. An inverse relationship was seen between wall thickness and a-tocopherol, vitamin C or b-carotene intake, supporting the hypothesis that dietary vitamin C and a-tocopherol may protect against atherosclerotic disease, especially in individuals >55 years old (Kritchevsky et al., 1995). However, in the asymptomatic age-, sex-, race-, and field center-matched case-control pairs selected from the ARIC study cohort, b-carotene, retinol, and a-tocopherol were unrelated to IMT (Iribarren et al., 1997). In middle-aged women, an inverse association was found between both the intake amount and plasma concentration of vitamin E and preclinical carotid atherosclerosis as measured by high-resolution B-mode ultrasound, supporting the hypothesis that low vitamin E intake is a risk factor for early atherosclerosis (Iannuzzi et al., 2002). In the EVA trial (Etude sur le Vieillisement Arteriel) which involved a total of 1389 French subjects for a 4-year period, increased levels of vitamin E was found to be significantly associated with less thickening of the arterial wall (BonithonKopp et al., 1997). In the Kupio Ischemic Heart Disease Study in which the relation between vitamin E and b-carotene plasma levels and the status of carotid IMT was examined over 12 months in 216 men with high LDL cholesterol levels, a very significant inverse correlation between the progression of carotid artery narrowing and the vitamin E plasma levels as well as those of b-carotene was observed (Salonen and Salonen, 1993). In the Antioxidant Supplementation in Atherosclerosis Prevention (ASAP) study, the effect of vitamin E and C on 3-year progression of carotid atherosclerosis in a randomized sample of 520 smoking and nonsmoking men and postmenopausal

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women with serum cholesterol P5.0 mmol/L were studied (Salonen et al., 2000). Atherosclerotic progression, as measured by IMT, was reduced by 74% in the male population receiving the formulation with both vitamins. No effect on the arterial wall thickness has been found in the female group. No improvement of carotid IMT or lumen diameter and even suggested deleterious effects were found after long-term daily nutritional dose supplementation with antioxidant vitamins and minerals (120 mg vitamin C, 30 mg vitamin E, 6 mg b-carotene, 100 lg selenium and 20 mg zinc) (Zureik et al., 2004). Using data from the Cholesterol Lowering Atherosclerosis Study (CLAS) (Blankenhorn et al., 1987), the association of self-selected supplementary antioxidant vitamin intake on the rate of progression of early preintrusive atherosclerosis was measured (Azen et al., 1996). Less carotid IMT progression was found for high supplementary vitamin E users (P100 IU per day) when compared with low vitamin E users (0.008 mm/y versus 0.023 mm/y), and no effect of vitamin E within the group receiving lipid-lowering drugs was found. The Study to Evaluate Carotid Ultrasound changes in patients treated with vitamin E (SECURE) (Lonn et al., 2001), a sub-study of the HOPE trial, was a prospective, double-blind trial that evaluated the effects of long-term treatment with the angiotensin-converting enzyme inhibitor ramipril and vitamin E on atherosclerosis progression in high-risk patients. However, in this study no differences in atherosclerosis progression rates were seen as evaluated by IMT between patients on vitamin E and those on placebo. In a further study measuring the relationship between carotid maximum intimamedia thickness (IMTmax), an index of atherosclerotic extension/severity, and plasma levels of c-tocopherol, a-tocopherol, lycopene, b-carotene and ubiquinone, IMTmax was only reduced with lycopene (Gianetti et al., 2002). In a study carried out with male monkeys (Macaca fascicularis) fed a cholesterol enriched diet, the thickness of carotid artery was significantly lower after 36 months of vitamin E treatment, as compared to the control group (Verlangieri and Bush, 1992). Reduced concentrations of plasma peroxides and less aortic intimal thickening compared with controls were measured in chickens fed high doses of a-tocopherol (Smith and Kummerow, 1989). Reduced restenosis after angioplasty in rabbits with established experimental atherosclerosis was seen following a-tocopherol supplementation, and the minimum luminal diameter was decreased, whereas the cross-sectional area of the intimamedia was greater in the untreated group than in the group receiving a-tocopherol 19 days before angioplasty. (Lafont et al., 1995). The incidence of coronary artery restenosis after angioplasty is also reduced by a-tocopherol supplementation in patients following percutaneous transluminal coronary angioplasty (PTCA) supplemented with 1200 IU/day of a-tocopherol for 4 months (DeMaio et al., 1992). The formation of neointima induced by vascular injury was decreased by c-tocoperol, but not by a-tocopherol in insulin resistant rats, possibly as a result of the reduction of nitrosative stress (Takahashi et al., 2006). In conclusion, the majority of these studies indicate that vitamin E protects against carotid thickening as measured by IMT, possibly reflecting direct or indirect

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effects of vitamin E on the cells of the vascular system, ultimately leading to reduced proliferation of VSMC.

4. Modulation of the vascular system cells involved in atherosclerosis by vitamin E Major cellular participants involved in atherosclerotic lesions development include endothelial cells, vascular smooth muscle cells (VSMC), monocytes/macrophages, T lymphocytes, mast cells, dendritic cells, adventitial fibroblasts, and platelets (Kelley et al., 2000; Li and Sun, 2007; Ross, 1995). Their activation results in alterations of signal transduction and gene expression, leading to increased proliferation, migration, apoptosis, uptake of cholesterol and lipids by scavenger receptors, and to increased production of reactive oxygen and nitrogen species (ROS and RNS), release of hydrolytic enzymes, inflammatory cytokines, chemokines, and growth factors that can produce vascular repair or further injury. Vitamin E has been described to affect many cellular events with possible impact on atherosclerosis (reviewed in Chan, 1998; Devaraj and Jialal, 1998; Munteanu et al., 2004b). In the following the regulatory effects of vitamin E on the cells of the vascular system are reviewed; albeit these effects were often assessed only in vitro, they may also reveal the molecular and cellular mechanisms playing a role in the prevention of atherosclerosis in vivo. 4.1. Modulation of endothelial cells by vitamin E Endothelial cells play an important role in the maintenance of vascular homeostasis. These cells function as a barrier to plasma components (e.g. lipoproteins and albumin) and to blood cells such as monocytes/macrophages, erythrocytes and T cells. Injury of this barrier by oxLDL, oxidative stress or possibly by harmful environmental agents such as polyhalogenated aromatic hydrocarbons is one of the early events of atherosclerosis and allows the blood components to enter the arterial wall in an uncontrolled manner. Endothelial cells also mediate the regulated interaction with inflammatory cells via binding to cell adhesion molecules and thus control their attachment and migration into the subendothelial space. Furthermore, endothelial cells are involved in the controlled transport of nutrients and other plasma components such as LDL or albumin into the vascular wall (Chan and Tran, 1990). Selective uptake from HDL by scavenger receptor SR-BI mediates the delivery of vitamin E across endothelial cell layers, e.g. at the blood-brain barrier (Goti et al., 2000, 2001); preferential uptake of c-tocopherol over a-tocopherol suggests the involvement of further specific transport proteins (Tran and Chan, 1992). Moreover, endothelial cells produce the so-called endothelium-derived relaxing factor, later identified as nitric oxide (NO), synthesized by endothelial nitric oxide synthase (eNOS), which modulates the contraction of VSMC by influencing guanylate cyclase and thus regulates the vascular tone. NO exerts also anti-thrombogenic, anti-proliferative effects, and influences the myocardial contractility. NO reaction

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with reactive oxygen radicals (ROS) yielding peroxinitrite (ONOO) is a major mechanism of reduced NO availability. 4.1.1. Vitamin E prevents apoptosis and increases the survival of endothelial cells Alterations of the above described endothelial cell functions play several roles during atherosclerosis development. Over the last two decades, vitamin E has been shown to normalize a number of pro-atherogenic changes in endothelial cells (reviewed in Devaraj and Jialal, 1998). Contrary to VSMC, the proliferation of endothelial cells is stimulated by vitamin E, what may accelerate the repair of injured endothelial cell layers (Kuzuya et al., 1991b; Ulrich-Merzenich et al., 2002). Several studies show that vitamin E prevents endothelial damage resulting from reactive oxygen species (ROS), oxLDL or lipid peroxides (Hennig et al., 1988; Keaney et al., 1996; Kuzuya et al., 1991a; Suttorp et al., 1986). Oral vitamin E supplementation raises LDL a-tocopherol content, increases LDL resistance to oxidation, and decreases the cytotoxicity of oxLDL to cultured vascular endothelial cells (Belcher et al., 1993). a-Tocopherol and trolox block the early intracellular events (TBARS and calcium rises) elicited by oxLDL or linoleic acid hydroperoxide in cultured endothelial cells (Mabile et al., 1995; Sweetman et al., 1995). oxLDL and oxysterols-induced necrosis and/or apoptosis of vascular endothelial cells is associated with increased caspase-3 activity and the generation of intracellular ROS. Whereas both of these effects are attenuated by a-tocopherol, b-tocopherol has no effect on caspase-3 activity, but it decreases the generation of ROS to the same extent as a-tocopherol, suggesting that a-tocopherol may inhibit caspase-3 activity in a non-antioxidant manner (Uemura et al., 2002). The inflammatory action of oxLDL in the vascular wall is enhanced by C. pneumoniae infection, leading to cell necrosis rather than apoptosis, what is prevented by vitamin E via inhibition of ROS production and promotion of endothelial cell survival (Nazzal et al., 2006). High glucose and advanced glycation endproduct (AGE) can also mediate toxicity to aortic endothelial cells, inhibit their proliferation and migration following wounding, and these events are prevented by vitamin E (Zhang et al., 2006). Similar to that, oxidative stress induced by hypertension in rats or by high glucose in coronary microvascular endothelial cells (CMEC) is prevented by vitamins C and E (Ulker et al., 2003, 2004). Lipopolysaccharide (LPS)-induced apoptosis in human endothelial cells is also prevented by vitamins C and E by modulation of Bcl-2 and Bax levels (Haendeler et al., 1996). The combination of vitamin E and a-lipoic acid increases endothelial cell Bcl-2 what may provide protection against apoptosis (Marsh et al., 2005). Endothelial VEGF and VEGFR-2 over-expression induced by high cholesterol LDL (HC-LDL) is prevented by vitamins C and a- or b-tocopherol both at mRNA and protein levels (Rodriguez et al., 2005), what is also seen by tocotrienols using DNA chip analysis of endothelial cells (Nakagawa et al., 2004). 4.1.2. Vitamin E modulates adhesion molecules expression on endothelial cells Several pro-atherogenic triggers can induce the expression of adhesion molecules on endothelial cells leading to increased attachment of inflammatory cells, and

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vitamin E has been shown to decrease both attachment and adhesion molecule expression. The expression of adhesion molecules such as VCAM-1 and ICAM-1 on endothelial cells is induced by oxLDL; this induction can be prevented by pretreatment with a-tocopherol (Cominacini et al., 1997). Similar to that, a-tocopherol inhibits LDLinduced expression of adhesion molecules and adhesion of monocytes to human aortic endothelial cells in vitro (Martin et al., 1997). The activation of endothelial cells by high levels of LDL-cholesterol and pro-inflammatory cytokines is inhibited by atocopherol, as seen by a reduction of the expression of chemokines and cell surface adhesion molecules, and the adhesion of leukocytes to endothelial cells (Meydani, 2004). Vitamin E inhibits lipid peroxidation-induced adhesion molecule expression in endothelial cells and decreases soluble cell adhesion molecules (sCAMs) such as sE-selectin, sVCAM, and sICAM in healthy subjects treated with increasing doses of a-tocopherol up to 800 IU/ml for 12 weeks (van Dam et al., 2003). Homocysteine-induced expression of adhesion molecules (VCAM-1, E-selectin) on human aortic endothelial cells and consequent adhesion of monocytic cells is inhibited by vitamin E (Koga et al., 2002). The adhesion of monocytes to endothelial cells, stimulated with agonists of monocytic cell adhesion, such as IL-1, lipopolysaccharide (LPS), thrombin, or phorbol 12-myristate 13-acetate (PMA), is also inhibited by atocopherol, via reduction of E-selectin mRNA and cell surface expression (Faruqi et al., 1994). Enrichment of human aortic endothelial cells (HAEC) with vitamin E suppressed IL-1b-stimulated expression of intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), and endothelial leukocyte adhesion molecule-1 (E-selectin), as well as the production of monocytes chemoattractant protein 1 (MCP-1) and IL-8 (Wu et al., 1999). Both ICAM-1 and VCAM-1 are downregulated by a-tocopherol in IL-1b-stimulated endothelial cells and neutrophils (Yoshikawa et al., 1998; Zapolska-Downar et al., 2000). Supplementation of hypercholesterolemic New Zealand white rabbits with vitamin E leads to in vivo down-regulation of endothelial cell adhesion molecules expression (ICAM-1 and VCAM-1) and macrophage accumulation in the aortas (Koga et al., 2004). 25-Hydroxycholesterol, an oxysterol, can enhance the monocyte adherence to human aortic endothelial cells (HAEC) by increasing the expression of vascular cell adhesion molecule-1 (VCAM-1). Compared to a-tocopherol, d-tocotrienol exerts the highest inhibitory action on monocytic cell adherence, possibly as a result of higher uptake (Naito et al., 2005). Similar to that, when compared to a-tocopherol and a-tocopheryl succinate, a-tocotrienol displays a more profound inhibitory effect on adhesion molecule expression (ICAM-1, E-selectin, VCAM-1) and monocytic cell adherence induced by TNF-a (Theriault et al., 2002). In these experiments, the inhibition of monocyte-endothelial cell adhesion by a-tocotrienol is reversed with the addition of mevalonate intermediates, suggesting that the inhibition of HMG-CoA reductase (HMGR) by a-tocotrienol may be involved. This is supported by greater HMGR inhibition and protein prenylation observed with d-and c-tocotrienols compared to a-tocotrienol, with consequent increased inhibition of monocyte adhesion and endothelial adhesion molecule expression (VCAM-1 and E-selectin) in TNF-a activated endothelial cells. This inhibitory action is reversed by co-incubation with

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farnesol and geranylgeraniol, suggesting a role for prenylated proteins in the regulation of monocyte adhesion (Chao et al., 2002). The increased intracellular accumulation of a-tocotrienol when compared to a-tocopherol may also play a role in the higher potency of a-tocotrienol to inhibit the adhesiveness of endothelial cells (Noguchi et al., 2003). 4.1.3. Vitamin E modulates angiogenesis by endothelial cells Atherogenesis is often associated with neovascularization (reviewed in Herrmann et al., 2006). Angiogenesis by human microvascular endothelial cells in three-dimensional gel in culture requires the production of interleukin IL-8, and vitamin E could reduce IL-8 production and angiogenesis (Tang and Meydani, 2001). The tocotrienols, but not the tocopherols, inhibit both the proliferation and vascular endothelial growth factor-stimulated tube formation of endothelial cells, with d-tocotrienol showing the highest activity (Inokuchi et al., 2003; Miyazawa et al., 2004). d-Tocotrienol, but not a-tocopherol reduces the vascular endothelial growth factor (VEGF)-stimulated tube formation by human umbilical vein endothelial cells (HUVEC), and inhibits the new blood vessel formation on the growing chick embryo chorioallantoic membrane. In contrast to that, a-tocopherol does not affect angiogenesis in HUVEC stimulated by tumor necrosis factor alpha (TNF-a) or phorbol 12-myristate 13-acetate (PMA), but nevertheless reduces intracellular ROS production (Navarra et al., 2006). 4.1.4. Vitamin E modulates endothelial-derived nitric oxide production Nitric oxide (NO) is a central regulator of vascular tone and homeostasis, and a reduction of NO bioavailability leads to endothelial dysfunction. NO is generated upon activation of endothelial NO synthase (eNOS), which is mediated by an increase of intracellular calcium and/or by eNOS phosphorylation. In human umbilical vein endothelial cells (HUVEC), a-tocopherol increases ionomycin-stimulated phosphorylation of eNOS at serine 1177, and tissue saturation with L-ascorbic acid is necessary to provide optimal conditions for endothelial NO formation (Heller et al., 2004). Similar to that, vitamins C and E treatment improves the endothelium-dependent vasomotor capacity and prevents decreased expression of eNOS in hypercholesterolemic pigs (Rodriguez et al., 2002). Vitamin E prevents lysophosphatidylcholine (LPC)-induced endothelial dysfunction and preserves endothelial NO release via suppression of the PKC and LPCinduced NF-jB activation in endothelial cells (Murohara et al., 2002; Sugiyama et al., 1998). Similar to that, activation of NF-jB, STAT1 and STAT3 transcription factors by oxLDL is prevented by a-tocopherol in endothelial cells (Maziere et al., 1999, 1996). Fatty acid (linoleic acid and other omega-6 fatty acids) activation of NF-jB in vascular endothelial cells is blocked by pre-enrichment with a-tocopherol (Hennig et al., 2000). Furthermore, a-tocopherol attenuates oxLDL-mediated degradation of IjBa and activation of NF-jB (p65) and inhibits the upregulation of angiotensin type 1 receptor (AT1R) mRNA and protein (Li et al., 2000b,c). Endothelial dysfunction is a phenomenon often observed in diabetic patients, which is an important cause for vascular complications during diabetes mellitus

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(reviewed in Haidara et al., 2006). Hyperglycemia in diabetic patients can lead to excessive amounts of superoxide radicals and this can interfere with NO production with consequent diminished NO-dependent vasodilatation and vascular complications. Similar to the anti-diabetic drug troglitazone, a-tocopherol increases eNOS protein and mRNA expression in human umbilical vein endothelial cells thus counteracting impaired vasodilatation (Goya et al., 2006). The peptide endothelin is the natural counterpart of endothelium-derived NO; a-tocopherol, but not b-tocopherol, inhibits thrombin-induced PKC activation and endothelin secretion in endothelial cells (Martin-Nizard et al., 1998), by suppressing diacylglycerol (DAG) level as a result of increasing DAG kinase activity (Tran et al., 1994b). In addition to NO, vasodilator prostanoids constitute a protective mechanism in maintaining normal vasomotor function. Vitamin E increases the production of vasodilator prostanoids prostaglandin I2 (PGI2; prostacyclin) and prostaglandin E2 (PGE2) by human aortic endothelial cells (HAEC). This is associated with upregulation of cytosolic phospholipase A2 (cPLA2) expression and arachidonic acid release, whereas the cyclooxygenases (COX-1 or COX-2) are inhibited at the post-translational level, leading to a net increase in the production of vasodilator prostanoids (Wu et al., 2004; Wu et al., 2005). Vitamin E stimulates phospholipase A2 with consequent increased arachidonic acid release (Tran and Chan, 1988, 1990), and enhances the acylation of 1-O-alkyl-sn-glycero-3-phosphocholine, the precursor of plateletactivating factor (PAF) in human endothelial cells (Tran et al., 1994a). Whereas the production of prostacyclin is stimulated by a-tocopherol, plasminogen activator and von Willebrand factor activity are markedly reduced (Huang et al., 1988; Tran and Chan, 1990). Vitamin E also restores reduced prostacyclin, PGE2 and thromboxane A2 synthesis resulting from exposure to high glucose (Kunisaki et al., 1992). The metabolite of a-tocopherol, a-CEHC, suppresses TNFa-stimulated nitrite production in endothelial cells, whereas LPS-stimulated microglial nitrite efflux is inhibited by both a-CEHC and c-CEHC (Grammas et al., 2004). 4.2. Modulation of vascular smooth muscle cells by vitamin E Many in vitro studies with cultured vascular smooth muscle cells (VSMC) isolated from animals and humans have been performed (reviewed in Zingg and Azzi, 2007). Cultured VSMC resemble de-differentiated, intimal cells thus representing predominantly migrating VSMC in their ‘‘proliferative phase’’, mostly involved in atherosclerosis progression. Not many studies address the effects of vitamin E on differentiated, resting VSMC in their ‘‘synthetic phase’’, resembling the contractile VSMC of the media. Among the cellular effects of vitamin E on VSMC (Table 2), the inhibition of proliferation is probably the most important one. Direct evidence for a-tocopherol inhibition of VSMC proliferation comes mainly from in vitro experiments; only few data are available using VSMC density as marker for their in vivo proliferation (besides IMT as marker for VSMC proliferation, Section 3.3). In vitro, VSMC growth arrest is induced by a-tocopherol via inhibition of protein kinase C activity (PKC) (Boscoboinik et al., 1991; Mahoney and Azzi, 1988; Tasina-

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Table 2 Modulation of vascular smooth muscle cells by vitamin E Cellular processes modulated by vitamin E in VSMC and possible effects on atherosclerosis

Molecular and cellular action of vitamin E in VSMC (examples, see also text)

Scavenging of free radicals in VSMC

Reduction of the oxidation of LDL to oxLDL, less lipid peroxides and oxidized proteins, inhibition of oxLDLinduced signal transduction and gene expression, inhibition of proliferation and inflammation (see text, Sections 3.2, 3.3 and 4.2)

Inhibition of VSMC proliferation and prevention of vascular narrowing

Reduction of VSMC proliferation by inhibition of protein kinase C (PKC) (see text, Sections 3.3 and 4.2)

Inhibition of oxLDL uptake in VSMC leading to prevention of foam cell formation

Reduced oxLDL uptake via inhibition of CD36 and SR-BI scavenger receptor expression in VSMC (Devaraj et al., 2001; Ricciarelli et al., 2000a; Teupser et al., 1999; Venugopal et al., 2004)

Inhibition of VSMC migration leading to prevention of vascular narrowing

Probucol and a-tocopherol suppressed VSMC migration and proliferation induced by high glucose (Yasunari et al., 1999). In human coronary VSMC, lysophosphatidylcholine (lyso-PC)-induced VSMC migration was inhibited by a-tocopherol (Kohno et al., 1998)

Inhibition of secretion of cytokines and extracellular matrix in VSMC, prevention of mononuclear cell infiltration, reduction of inflammation. Prevention of de-stabilization of the fibrous plaque

a-Tocopherol activated cellular release of TGFb with consequent growth inhibition (Ozer et al., 1995). Vitamin E increased the expression of the connective tissue growth factor involved in the production of collagen I and fibronectin, with consequent stabilization of the atherosclerosic plaque (Villacorta et al., 2007, 2003). The combination of vitamin E and C was able to increase collagen content making the aortas less prone to rupture (Orbe et al., 2003). Both, the expression and activity of the collagenase (MMP-1) were inhibited by vitamin E, possibly reducing plaque de-stabilization (Orbe et al., 2003; Ricciarelli et al., 1999)

Inhibition of apoptosis of VSMC Prevention of de-stabilization of the fibrous plaque

a-Tocopherol was significantly more effective than ctocopherol in reducing oxLDL-induced apoptosis (de Nigris et al., 2000a). On the contrary, certain tocopherol analogues (a-tocopherylsuccinate, a-tocopheryloxalate and a-tocopherylmalonate) induced apoptosis in VSMC (Kogure et al., 2004). a-Tocopherol attenuated significantly the Ab-induced cytotoxicity in VSMC (Munoz et al., 2002)

Inhibition of contraction of VSMC

Vitamin E prevented endothelial dysfunction associated with cholesterol feeding (Stewart-Lee et al., 1994), restored the otherwise reduced vasodilator vascular responses to acetylcholine in cholesterol fed rabbits (Klemsdal et al., 1994), induced concentration-dependent relaxations of cerebral arteries (Li et al., 2001), and increased the ethanol induced elevation of intracellular Ca2+ (Zheng et al., 1998) (continued on next page)

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Table 2 (continued) Cellular processes modulated by vitamin E in VSMC and possible effects on atherosclerosis

Molecular and cellular action of vitamin E in VSMC (examples, see also text)

Modulation of signal transduction and gene expression in VSMC, normalization of aberrant gene expression

Vitamin E is modulating a number of genes playing a role in atherosclerosis development (reviewed in Azzi et al., 2004; Munteanu et al., 2004b; Villacorta et al., 2007; Zingg and Azzi, 2004). a-Tropomyosin is up-regulated by atocopherol in rat VSMC (Aratri et al., 1999). The expression of the connective tissue growth factor (CTGF) is increased by a-tocopherol in VSMC cell lines and primary VSMC (Villacorta et al., 2003). The activity and mRNA level of superoxide dismutases (SOD) in rat aortic VSMC (A7r5) cells for 2 days increased with a-tocopherol and later decreased (Huang et al., 1999)

to et al., 1995); later studies showed that in VSMC protein kinase C alpha (PKCa) activity is inhibited as a result of activation of protein phosphatase 2A (PP2A) by atocopherol, whereas the other tocopherols have weaker effects (Azzi et al., 1998, 2001; Cachia et al., 1998; Martin-Nizard et al., 1998; Neuzil et al., 2001; Ricciarelli et al., 1998). These in vitro studies collectively suggest that a-tocopherol retards narrowing of the artery lumen by inhibiting VSMC proliferation as a consequence of indirect inhibition of PKC in a non-antioxidant manner. In vivo, inhibition of VSMC proliferation as measured by VSMC density was described in Watanabe heritable hyperlipidemic (WHHL) rabbits, where vitamin E reduced early lesions, VSMC density, and the immunohistochemical presence of cMyc which co-localized with oxLDL/foam cells in the coronary arteries (de Nigris et al., 2000b). In male Otsuka Long-Evans Tokushima Fatty (OLETF) rats, an experimental model of type 2 diabetes mellitus, a-tocopherol and troglitazone normalized the increased level of the actual medial area and the number of VSMC (Shinomiya et al., 2002). Rats receiving a 0.5% vitamin E plus 1% cholesterol diet showed a reduced neo-intimal thickening after balloon injury compared to animals receiving either cholesterol alone, or a control chow diet. The intimal lesions consisted predominantly of VSMC and few monocytes/macrophages (<0.5%). In vitro, vitamin E dose-dependently inhibited mitogenesis induced by platelet-derived growth factor (PDGF) or serum (2%), in both adult rat thoracic aortic VSMC and embryonic rat aortic VSMC (A7r5) (Konneh et al., 1995). In another study, Watanabe Heritable Hyperlipidemic (WHHL) rabbits were fed different antioxidants (a-tocopherol, probucol, ubiquinone-10) for 12 months, and aortic lesions were analyzed for their extent and cellular composition, mean thickness of fibrous caps and density of VSMC therein, content of antioxidants, non-oxidized and oxidized lipids. Probucol significantly lowered the extent and macrophage content of lesions, however, it increased the existence and VSMC density of fibrous caps possibly resulting from inhibition of apoptosis. a-Tocopherol supplementation increased the aortic content of vitamin E, but had no decreasing effect on either the

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accumulation of macrophage-specific antigen in the aorta or lesion size. Nevertheless, both probucol and a-tocopherol significantly decreased in vitro LDL oxidizability, measured under typically strong oxidative conditions (Brasen et al., 2002). Since oxidation of LDL to oxLDL increases VSMC proliferation and DNA synthesis at low, non-cytotoxic oxLDL concentrations (Chatterjee, 1992), the prevention of oxLDL formation by a-tocopherol is expected to lead to inhibition of cell proliferation (reviewed in Chisolm and Chai, 2000). In quiescent rabbit VSMC cultures, oxLDL and lysophosphatidylcholine (lysoPC) induced over a 10-fold increase in DNA synthesis above that in untreated cells, whereas a-tocopherol pre-treatment normalized the oxLDL- and lysoPC-induced VSMC proliferative responses (Chai et al., 1996; Lafont et al., 1995). However, in these experiments the increased cell proliferation in response to oxLDL treatment appears to be the result of oxidative stress, since it could be inhibited by several antioxidant enzymes, including superoxide dismutases and catalase (Oinuma et al., 1997; Stiko et al., 1996). DNA synthesis was stimulated by oxLDL in rabbit VSMC, suggesting that oxidized lipids can trigger hyperplasia, and a-tocopherol limits this effect by inhibiting either oxidation, or by interfering with cellular signalling caused by oxidized lipids. In support for the latter, vitamin E fully prevented cholesterol-induced atherosclerotic lesions in rabbits and the induction of PKC activity while the potent antioxidant probucol was not effective. In this study, the rabbits received a vitamin E poor diet containing 2% cholesterol or 2% cholesterol in the diet plus 50 mg/kg vitamin E intramuscularly or 1% probucol or 50 mg/kg vitamin E plus 1% probucol for 4 weeks. These results show that the protective effect of vitamin E against hypercholesterolemic atherosclerosis is not produced by another antioxidant such as probucol and, therefore, may not be linked to the antioxidant properties of vitamin E (Ozer and Azzi, 2000). Vitamin E may also reduce VSMC hyperplasia induced by oxLDL by inhibiting CD36 scavenger receptor expression in VSMC, with consequent reduced oxLDL-VSMC interaction, oxLDL uptake and oxLDL-mediated signal transduction (Munteanu et al., 2006; Ricciarelli et al., 2000a). In vivo, the effects of oxLDL on VSMC in rabbits were studied by local application at the level of the vascular wall. Intimal thickening was induced by placing a silicone collar around the carotid arteries during 2 weeks. The collar was connected to an osmotic minipump containing human oxLDL, LDL or phosphate-buffered saline. Collar placement resulted in a thickening of the intima with the appearance of smooth muscle a-actin positive VSMC. Perivascular infusion of LDL or oxLDL significantly enhanced the intima, containing large amounts of T-lymphocytes, collagen and VSMC. These results show that the local application of oxLDL in vivo promotes intimal thickening and impairs the endothelium-dependent relaxations, thereby supporting the suggestion that oxLDL plays an important role in the morphological and functional changes present in atherosclerotic blood vessels (Herman et al., 1999) that possibly can be prevented by inhibition of LDL oxidation by vitamin E. In addition to oxLDL and other pro-inflammatory triggers such as bacteria and viruses leading to hyper-proliferation of VSMC, progression of atherosclerosis may also be facilitated by specific genetic and epigenetic mutations and polymorphisms in genes that favour proliferation, in a similar manner as occurs with oncogenes or

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tumour suppressor genes during cancer development (Stein et al., 2002; Topol et al., 2006; Zingg and Jones, 1997). In fact, mutations have been found in the TGFb type II receptor gene, and active TGFb is decreased in advanced atherosclerosis, possibly favouring hyper-proliferation of VSMC (Grainger et al., 1995; McCaffrey et al., 1997). Similar to that, mutations in the p53 gene accelerate atherosclerosis by increasing cell proliferation of monocytes/macrophages and of VSMC (Guevara et al., 1999). Epigenetic changes as seen for example by alterations of DNA methylation patterns may also contribute to the development of atherosclerosis (Dong et al., 2002). In atherosclerotic lesions, genome-wide hypomethylation and gene-specific hypermethylation were observed already in early stages of atherosclerosis, and possible reasons such as increased plasma levels of homocysteine, atherogenic lipoproteins or increased VSMC proliferation have been recently discussed (Lund et al., 2004; Zaina et al., 2005a,b). In particular the estrogen receptor alpha and beta genes are inactivated by hypermethylation during ageing and in atherosclerotic lesions (Kim et al., 2007; Post et al., 1999; Ying et al., 2000), and atherogenic lipoproteins promote genome-wide DNA hypermethylation in THP-1 monocytes (Lund et al., 2004). It remains to be investigated whether vitamin E can normalize cell proliferation resulting from genetic and epigenetic mutations. 4.3. Modulation of monocytes, macrophages and T cells by vitamin E Atherosclerosis is broadly recognised as an inflammatory response of monocytes/macrophages and lymphocytes to modified lipoproteins intruded into the arterial wall (Li and Glass, 2002). Some responses of macrophages appear being protective, such as the clearance of oxidized lipoproteins and the efflux of lipoprotein-derived cholesterol to high-density lipoprotein (HDL) acceptors for reverse cholesterol transport. However, hypercholesterolemic mice bred to macrophage deficient ones become highly resistant to atherosclerosis (Smith et al., 1995), indicating that the net contribution of macrophages to the atherosclerotic process promote lesion initiation and progression. Monocytes-derived macrophages were proven to be the principal source of foam cells in the atherosclerotic lesion due to their ability of taking up modified lipids and lipoproteins through scavenger receptors (Goldstein et al., 1979). Moreover, macrophages can oxidize LDL by generating ROS and RNS via NADPH-oxidase, lipooxygenase, myeloperoxidase or nitric oxide synthase (reviewed in Ross, 1995). In atherosclerotic lesions, many proinflammatory cytokines, such as interleukins (IL-1, IL-6, IL-8, IL-10, IL-12) and tumor necrosis factor (TNFa), are released by macrophages in response to infiltrated lipoproteins (reviewed in Takahashi et al., 2002). Activated macrophages can stimulate blood circulating monocytes, (e.g. by producing agents that induce monocyte proliferation M-CSF, GM-CSF), and other pro-atherogenic processes such as smooth muscle proliferation (PDGF-AA, PDGFBB, HB-EGF, basic FGF, TGFb), endothelial proliferation (VEGF, FGF, TGFa) (Libby et al., 1989, 1986; Ross et al., 1990), growth inhibition (IFNc, IL-1, TGFb), and chemotaxis for other monocytes (M-CSF, GM-CSF, MCP-1, oxLDL), for

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endothelial cells (VEGF, bFGF), and for smooth muscle cells (TGFb, PDGF, FGF) (Ross, 1993a). Vitamin E has been shown to affect the monocytes and their release of ROS and lipid oxidation (Jialal et al., 2001), their expression of oxLDL-induced CD36 scavenger receptor (Munteanu et al., 2006), their adhesion to the endothelium by decreasing monocytic adhesion molecules expression, such as CD11b and VLA-4 (Devaraj et al., 1996; Islam et al., 1998; Jialal et al., 2001), and their trans-endothelial migration into the intima (Mine et al., 2002; Rattan et al., 1997). Whereas the proliferation of THP-1-monocytes was not affected by a-tocopherol, clear inhibitory effects were seen with a-tocopheryl phosphate (Munteanu et al., 2004c). At the macrophage level vitamin E affects the uptake and export of cholesterol and lipids via scavenger receptors (Devaraj et al., 2001; Devaraj and Jialal, 1998) (Sections 5.1 and 5.2). As expected, vitamin E prevents oxidation of LDL by macrophages, an effect exerted both by scavenging free radicals and by specifically interacting with the activity and expression of enzymes involved in this process. a-Tocopherol, and not b-tocopherol or trolox, inhibits the activity of PKC from monocytes, followed by inhibition of phosphorylation and translocation of the cytosolic factor p47(phox) resulting in an impaired assembly of the NADPH-oxidase with consequent lower superoxide production (Cachia et al., 1998; Islam et al., 1998). An additional possible mechanism of LDL protection from oxidation by vitamin E in the sub-endothelial space could be the maintenance or the augmentation of paraoxonases activity (PON1, possibly PON2 and PON3), which are HDL-associated esterases that can hydrolyze and reduce lipid peroxides in lipoproteins and in arterial cells (Aviram et al., 2005). Oxysterols, particularly those oxidised at position 7 (7b-hydroxycholesterol), induce apoptosis in cell types such as vascular endothelial cells, VSMC and monocytes and their level in plasma has been positively associated with an increased risk of atherosclerosis. a- and not c-Tocopherol or a-tocopheryl-acetate was able to decrease 7 b-hydroxycholesterol induced apoptosis in human U937 monocytes, suggesting for this effect a non-antioxidant mechanism (Lyons et al., 2001). a-Tocopherol therapy, especially at high doses, reduced the release of pro-inflammatory cytokines, including IL-1b, IL-6, TNF-a, and the chemokine IL-8 (Devaraj and Jialal, 1999; Jialal et al., 2001) (reviewed in Singh and Jialal, 2004). The reduction of IL-1b release induced by a-tocopherol was exerted through 5-lipooxygenase (5-LO) activity inhibition (Devaraj and Jialal, 1999). b-Tocopherol had no effect on 5-LO activity, suggesting a non-antioxidant mechanism for a-tocopherol. Activated macrophages are present in the shoulder regions of advanced atherosclerotic lesions, where rupture more often occurs. Epidemiological studies in humans indicating that the levels of circulating markers of inflammation, such as C-reactive protein (CRP) or plasminogen activator inhibitor-1 (PAI-1) are significantly linked with the risk of developing acute ischemic syndromes (Libby and Ridker, 2004), support the idea that inflammation underlies events leading to plaque rupture. a-Tocopherol has been shown to decrease CRP levels in patients with CVD, and PAI-1 levels were decreased by a-tocopherol supplementation in vivo (reviewed in Singh and Jialal, 2004).

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The expression of a variety of genes involved in inflammatory response and cellular proliferation is controlled by the nuclear factor kappa B (NF-jB) transcription factor. NF-jB is activated by a cholesterol-rich diet (Liao et al., 1993) and by oxLDL (Yan et al., 1994), and activated NF-jB has been identified in situ in human plaque, but not in normal vascular cells unaffected by atherosclerosis (Lindner and Collins, 1996). NF-jB regulates genes that are involved in atherosclerosis progression, including the genes of TNF-a, IL-1, macrophages or granulocyte colonies stimulating factor, monocyte chemotactic protein 1 (MCP-1), and of VCAM-1, and ICAM (Collins and Cybulsky, 2001; Rimbach et al., 2000). Experimental data suggest that the anti-inflammatory properties of vitamin E are partly a consequence of NF-jB activity inhibition. Studies carried out on human THP-1 macrophages treated with a-tocopheryl-succinate and activated afterwards have shown a 43% reduction of NF-jB activation as compared to the control cells. Whether vitamin E directly interferes with the activation of NF-jB, or influences NF-jB activity by adjusting the intracellular redox status, known as a major determinant of NF-jB activation, is still an open question (Rimbach et al., 2002). In mice exposed to short-term cigarette smoke, supplementation with a-tocopherol alone or in combination with L-ascorbic acid reduced the number of alveolar macrophages, lowered the macrophage metalloprotease-12 and TNF-a, as well as NF-jB activation in lung extracts, suggesting that the inflammatory process after cigarette exposures was reduced by L-ascorbic acid, a-tocopherol, or more efficiently by combined vitamin supplementations (Silva Bezerra et al., 2006). However, in a placebo-controlled, double blind study on healthy male subjects with normal L-ascorbic acid levels, a-tocopherol supplementation had no significant effects in monocyte CD11b expression, monocyte adhesion to endothelial cells, plasma C-reactive protein or sICAM-1 and there was no evidence for nuclear translocation of NF-jB in isolated resting monocytes (Woollard et al., 2006). In addition to monocytes/macrophages, T cells play an important role in atherosclerosis by interacting with and activating macrophages and VSMC, as well as by influencing the inflammatory balance between pro- and anti-inflammatory factors (reviewed in Robertson and Hansson, 2006). Not only monocytes/macrophages but also lymphocytes migrate into atherosclerotic lesions (Ross, 1993a,b, 1999). In early human atherosclerotic lesions, 10–20% of the infiltrated cells are T lymphocytes, mostly the CD4+ helper-inducer type, whereas the B cells are a minor population (Jonasson et al., 1986). IL-2 released by monocyte-derived macrophages stimulates lymphocyte proliferation, while the activated lymphocytes could produce IFNc, GM-CSF, or TNFa to activate and attract macrophages (Ross, 1993a). Macrophages, macrophage-derived foam cells and T cells express CD40 and CD40L, with macrophages and T cells being in close contact with each other, and administration of a neutralizing anti-CD40L antibody in cholesterol-fed LDLR-deficient mice reduces the development of atherosclerosis (Hakkinen et al., 2000). A number of studies report a protective and stimulating effect of vitamin E on T lymphocytes structure and activity, combined with an anti-inflammatory action. In human monocyte-derived macrophages, the concurrent suppression by vitamin E and C of two events triggered by the proinflammatory cytokine interferon-gamma

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(IF-c), the neopterin production and tryptophan degradation, suggests an effect of the vitamins on the formation and release of this cytokine by stimulated T cells (Winkler et al., 2007). In human T cells incubated with a-tocopheryl acetate or a-tocopheryl succinate, a concentration-dependent inhibition of NF-jB activation was observed (Suzuki and Packer, 1993). The Fas-mediated pathway which is activated by Fas ligand derived from activated macrophages is known of being able to induce apoptosis (Imanishi et al., 2002). Vitamin E suppresses Fas ligand (CD95L) mRNA expression and protects T cells from CD95-mediated apoptosis (Li-Weber et al., 2002). Rats treated with tocopherol showed an unchanged general structure of the thymus and of its content of lipid peroxydation products four weeks after intensive physical exercise, in contrast to animals receiving no supplementation (Sapin and Tkachuk, 2005). In T cells of mice, aging affects the expression of genes associated with signal transduction, transcriptional regulation, and apoptosis; vitamin E modulates the expression of several genes associated with cell cycle (Ccnb2, Cdc2, Cdc6) and Th1/Th2 balance in old T cells, and induces higher IL-2 up-regulation in young and old T cells and lower IL-4 up-regulation in old T cells following their stimulation (Han et al., 2006). As reviewed by Meydani et al., vitamin E enhances T-cell function by promoting cell division and IL-2 production of naı¨ve T-cells and by inhibiting macrophages in their production of the T-cell suppressive factor prostaglandin E2 (PGE2), but whether these events contribute to the initiation or propagation of atherosclerosis is not known (Meydani et al., 2005a). 4.4. Modulation of mast cells by vitamin E Coronary artery disease, cardiac events, inflammation and atherosclerosis are associated with elevated blood histamine and isoprostane (8-isoPGF2a) levels, suggesting the involvement of histamine producing cells (mast cells, monocytes/macrophages, T cells) in these diseases (Clejan et al., 2002; Schneider et al., 2002). Increased numbers of mast cells were found in atherosclerotic lesions when compared with normal intima, and these mast cells are often associated with macrophages and extracellular lipids (Jeziorska et al., 1997), in particular in fatty streaks and the shoulder regions of atheromas (Kaartinen et al., 1994). In human blood vessels, mast cells have been observed in the intima of carotic arteries at sites of hemodynamic stress, together with monocytes, T-lymphocytes, and dendritic cells (Waltner-Romen et al., 1998). It is still unclear, to what degree a higher density of mast cells in plaques is the result of increased recruitment or the consequence of higher proliferation (Frangogianni and Entman, 2000). Mast cells are activated by oxidized lipoproteins (oxLDL) resulting in increased expression of inflammatory cytokines such as interleukin 8 (IL-8) (Kelley et al., 2006), suggesting that the reduction of oxidation of LDL by vitamin E may also reduce mast cell activation. Moreover, activated mast cells can contribute to foam cells and fatty streak formation by stimulating LDL modification and uptake by macrophages (Kovanen, 1996), by secreting a variety of inflammatory mediators (histamine, cytokines, chemokines, leukotrienes, prostaglandins, platelet activating factor) and enzymes (tryptase, chymase, carboxypeptidase and cathepsin G)

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(reviewed in Kelley et al., 2000), possibly leading to weakening and rupture of atherosclerotic plaques (Leskinen et al., 2003). It can be assumed that mast cells signaling and proliferation are deregulated during the progression of atherosclerosis and normalization by vitamin E could play a beneficial role. In fact, proliferation of the HMC-1 mast cells line carrying activating mutations in the c-kit receptor is inhibited by treatment with tocopherols via inhibition of the c-kit/PI3K/PKB signal transduction pathway (Kempna et al., 2004), and several further effects of vitamin E on mast cells have been described (reviewed in Zingg, 2007b). In this context it is interesting to note that VSMC of the media were also found to express c-kit and stem cell factor (SCF), suggesting the existence of mast cell-VSMC interaction and of an autocrine and paracrine loop of c-kit and its ligand (stem cell factor) on the surface of VSMC (Miyamoto et al., 1997). Injured vessels revealed that c-kit expression within the media and neointima is significantly increased following injury (Hollenbeck et al., 2004) and during in-stent restenosis (Hibbert et al., 2004), suggesting that c-kit may play a role in vascular repair.

5. Modulation of signal transduction and gene expression by vitamin E in cells of the vascular system Changes of signal transduction and gene expression induced by environmental, nutritional, inflammatory, genetic or age-dependent factors, and mutations affecting the function and expression of specific genes may determine atherosclerotic progression (Noguchi, 2002; Zingg et al., 2000a). Moreover, age-dependent changes of signal transduction and gene expression could increase the incidence of atherosclerosis with advanced age. Vitamin E modulates signal transduction and gene expression in several cell types, and deranged gene expression during atherosclerosis could possibly be normalized by a-tocopherol (reviewed in Azzi et al., 2002; Munteanu et al., 2004b; Villacorta et al., 2007; Zingg, 2007a; Zingg and Azzi, 2004). In particular, the expression levels of the scavenger receptors in vascular cells but also in other tissues plays an important role in determining several atherogenic parameters (Stein et al., 2002; Zingg et al., 2000a,b). Over-expression of the CD36 scavenger receptor in monocytes/macrophages and VSMC increases oxLDL-uptake and foam cell formation, whereas over-expression of the scavenger receptors SR-BI/II increases reverse cholesterol transport by HDL from peripheral cells to the liver and subsequent release in the bile (reviewed in Lopez and McLean, 2006). The expression of several other genes with relevance for atherosclerosis is also modulated by vitamin E (reviewed in Munteanu et al., 2004b; Villacorta et al., 2007); in the following, the effects of vitamin E on the expression of the scavenger receptor genes are reviewed. 5.1. Scavenger receptors are induced by various stimuli Uncontrolled uptake of oxLDL and lipids ultimately converts monocytes/macrophages and VSMC to foam cells. In this process, scavenger receptors (SR-A, SR-BI/

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II and CD36) play a critical role due to their ability to bind oxLDL and their function in the transport of lipids and cholesterol into and out of the cells (Yamada et al., 1998b; Zingg et al., 2000a). These scavenger receptors are over-expressed at the atherosclerotic lesion; the expression of the SR-AI/II, SR-BI and CD36 scavenger receptors is increased in macrophages (Gough et al., 1999; Hirano et al., 1999; Nakata et al., 1999), and CD36 and LOX-1 are expressed in VSMC and endothelial cells (Hajjar and Haberland, 1997; Kataoka et al., 1999; Mulvihill et al., 2004; Ricciarelli et al., 2000b; Zingg et al., 2002). In the vascular wall, the CD36 scavenger receptor is mainly expressed in monocytes/macrophages and cultured human aortic smooth muscle cells. In addition to oxLDL and oxHDL, CD36 binds to a large variety of ligands: apoptotic cells (via externalized phosphatidylserine), thrombospondin, collagens type I and IV, fibrillar b-amyloid, anionic phospholipids, and high density lipoproteins (HDL). Moreover, in various tissues, the uptake of long chain fatty acids is mediated by CD36/FAT (Fatty Acid Translocase), and transgenic mice over-expressing CD36 have reduced blood lipids (Abumrad et al., 1998, 1993; Aitman et al., 1999; Febbraio et al., 1999; Febbraio et al., 2001; Guthmann et al., 1999; Thorne et al., 2007). Thus, whereas in the cells of the vascular wall over-expression of scavenger receptors increases atherosclerosis, in tissues other than the vascular wall it may be associated with reduced atherosclerosis, e. g. by lowering plasma lipids levels (Li et al., 2000a; Stein et al., 2002). Using stem cell transplantation, the absence of CD36 specifically in the monocytes/macrophages lineage was protective against atherosclerosis (Febbraio et al., 2004). Higher levels of CD36 expression in female liver as compared to male has been suggested to contribute to gender differences in susceptibility to diseases such as atherosclerosis, hyperlipidemia or insulin resistance (Stahlberg et al., 2004). A role of CD36 in native immunity and inflammatory processes in response to bacterial pathogens was recently suggested, since CD36 binds bacterial lipids (diacylglyceride and lipoteichoic acid) and modulates the Toll-like Receptors 2 and 6 (Hoebe et al., 2005). Thus, CD36 may act as a sensor for microbial lipids, thrombospondin and apoptotic cells either directly or possibly together with receptors able to initiate signal transduction, such as the Toll-like receptors. Mutations of CD36 cause a recessive immunodeficiency in which macrophages are insensitive to a diacylated bacterial lipopeptide (MALP-2) and to lipoteichoic acid (Hoebe et al., 2005). Mice homozygous for the mutation are hypersusceptible to Staphylococcus aureus infection (Stuart et al., 2005). In cell culture, CD36 recognizes both Gram-negative and Gram-positive bacteria, and mediates uptake of Escherichia coli and Staphylococcus aureus, and the related scavenger receptor SR-BI also recognizes Mycobacterium fortuitium and the Hepatitis C virus (Philips et al., 2005; Scarselli et al., 2002). Common bacteria, such as the peridontal pathogen Porphyromonas gingivalis, or Chlamydia pneumoniae, and viruses such as the Cytomegalo virus (CMV) have been suggested to accelerate the development of atherosclerosis (Gibson et al., 2004, 2006; Grayston et al., 1997; Gura, 1998; Lalla et al., 2003), and it appears possible that CD36 or other scavenger receptors play a role in recognizing these agents and triggering their cellular effects in the vascular wall. Whereas some scavenger receptors are upregulated by Chlamydia

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pneumoniae infection (Shi and Tokunaga, 2004; Yoshida et al., 2006), SR-BI is down-regulated by the phosphorylated lipid A portion of lipopolysaccharide (LPS), which is highly conserved among gram-negative microorganisms, including Chlamydia pneumoniae (Baranova et al., 2002). The relevance of CD36 expression in the onset of atherosclerosis has been proven in mice by disruption of the CD36 gene with consequent prevention of atherosclerotic lesion development (Febbraio et al., 2000). In line with that, human monocytes/macrophages from CD36 deficient patients showed a low capacity to bind and internalize oxLDL (Febbraio et al., 1999; Nozaki et al., 1995); these monocytes show also decreased NF-jB activation after oxLDL stimulation, leading to a lower expression of inflammatory cytokines (Janabi et al., 2000), suggesting a role of CD36 in oxLDL-stimulated signal transduction. In contrast to CD36, over-expression of the SR-BI/II scavenger receptors is suppressing atherosclerosis as a result of increased reverse cholesterol transport via HDL, and genetic ablation of SR-BI reduces the biosynthesis of steroid hormones from cholesterol in steroidogenic tissues and has negative effects on cardiovascular physiology (Lopez and McLean, 2006). In addition to controlling the cellular uptake and export of cholesterol, SR-BI/II mediates also the transport of vitamin E across enterocytes (Reboul et al., 2006), and from HDL across the blood-brain barrier and into cells of various peripheral tissues (Goti et al., 2000). In line with this, the reproductive pathologies in SR-BI knockout mice are believed to result from defective tissue uptake of vitamin E, thus mimicking the vitamin E deficient state with possible effects on atherosclerosis development (Lopez and McLean, 2006; Mardones and Rigotti, 2004; Mardones et al., 2002). At the molecular level, increased expression of scavenger receptors at the atherosclerotic lesion is possibly the result of a positive feedback loop mediated by oxLDL and its lipid content (Hajjar and Haberland, 1997; Han et al., 1997; Nagy et al., 1998; Nakata et al., 1999), or by several other triggers. CD36 expression is increased by oxLDL (Mikita et al., 2001; Tsukamoto et al., 2002), via the peroxisome proliferator receptor gamma (PPARc) and the NF-E2-related factor (Nrf2) (Ishii et al., 2004; Nagy et al., 1998; Tontonoz et al., 1998), leading to increased oxLDL uptake in THP1-derived macrophages (Sugano et al., 2001; Tsukamoto et al., 2002). Activation of CD36 by interleukin-4, 15-deoxyDelta(12,14) prostaglandin J(2), and oxLDL in murine macrophages is dependent on protein kinase C (PKC) and PPARc (Feng et al., 2000), whereas in THP-1 cells induction by retinoic acid is independent of PPARc and PKC (Han and Sidell, 2002). Cholesterol and cholesterol acetate increase CD36 expression possibly via activation of sterol regulatory binding proteins (SREBP-1/2) and subsequent activation of PPARc (Fajas et al., 1999; Han et al., 1999). 5.2. Inhibition of scavenger receptor expression by vitamin E and prevention of atherosclerosis In VSMC and monocytes/macrophages, the scavenger receptors SR-A-I/II, SRBI and CD36 are down-regulated by a-tocopherol (Devaraj et al., 2001; Mamputu et al., 2006; Ricciarelli et al., 2000a; Teupser et al., 1999; Witt et al., 2000). The role

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of a-tocopherol in diminishing scavenger receptor activity (CD36 and SR-BI) has been confirmed in vivo in several animal models (Barella et al., 2004; Fuhrman et al., 2002; Negis et al., 2006; Ozer et al., 2005; Witt et al., 2000). Correspondingly, rats depleted of vitamin E show increased expression of the scavenger receptor SRB1 as well as CD36 (Kolleck et al., 1999; Munteanu et al., 2006). At the molecular level, a-tocopherol reduces CD36 over-expression in human macrophages by reducing increased Tyk2 tyrosine kinase activity triggered by oxLDL (Venugopal et al., 2004). In fact, several studies indicate that tyrosine phosphorylation is modulated by the tocopherols. In oxLDL-stimulated MRC5 fibroblasts, tyrosine phosphorylation of JAK2, STAT1 and STAT3 is reduced by a-tocopherol (Maziere et al., 2001). In VSMC, angiotensin II-induced tyrosine phosphorylation of two major proteins (p120, p70) and ERK activation are markedly reduced by a-tocopherol, whereas ERK activation by epidermal growth factor is unaffected (Frank et al., 2000). Tyrosine phosphorylation is also decreased by a-tocopheryl succinate in human neutrophils via activation of a tyrosine phosphatase (Chan et al., 2001). Another protein kinase that is activated by oxLDL is protein kinase B (PKB); in VSMC, activation of PKB by oxLDL induces cell proliferation (Chien et al., 2003) and in mouse bone marrow derived macrophages, it increased survival by preventing apoptosis (Hundal et al., 2001). In THP-1 monocytes, oxLDL-induced CD36 overexpression is normalized by a-tocopherol via inhibition of oxLDL-induced activation of the PI3K/PKB/PPARc signalling pathway (Munteanu et al., 2006). Similar to that, the tocopherols interfere with PKB (Ser473) phosphorylation, leading to reduced proliferation of HMC-1 mast cells and several other cell lines (Kempna et al., 2004). In breast cancer cells, PKB phosphorylation is inhibited by tocotrienols after stimulation by EGF (Sylvester et al., 2002), and also by the two tocopherol derivatives, a-tocopheryl succinate and a-tocopheryl oxybutyric acid (Akazawa et al., 2002). c-Tocotrienol decreases the relative intracellular levels of the phosphorylated forms of PDK-1, PKB, and glycogen synthase kinase 3 (GSK-a/b) (Shah and Sylvester, 2004; Sylvester and Shah, 2005). In addition to effects on signal transduction, oxLDL reduces proteasome activity (Vieira et al., 2000), and increased levels of ubiquitinated proteins and decreased proteasome activity were detected in unstable atherosclerotic plaques (Herrmann et al., 2002; Versari et al., 2006). Recent evidence suggests that vitamin E can modulate proteasome activity (Munteanu et al., 2004a, 2005; Stolzing et al., 2006; Zingg and Azzi, 2006) and proteasome inhibition increases CD36 expression (Liang et al., 2004; Munteanu et al., 2004a, 2005); whether a-tocopherol can restore cellular proteasome activity after inhibition by oxLDL remains to be determined. 5.3. Over-expression of scavenger receptor CD36 by ritonavir is prevented by vitamin E Infection with the human immunodeficiency virus (HIV) is associated with increased oxidative stress as measured by the amount of lipid peroxidation, which was decreased by vitamin E and C in these patients (Allard et al., 1998; Lorenz et al., 2007). Moreover, the risk of premature atherosclerosis is increased in patients

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treated with anti-retroviral protease inhibitors (ARPI) caused by changes in several physiological and cellular events ultimately leading to hyperlipidemia, lipodystrophy, vascular inflammation, endothelial dysfunction and increased levels of oxLDL (Duong et al., 2006; Fisher et al., 2006; Spector, 2006; Sudano et al., 2006; Wang et al., 2007). One such ARPI, ritonavir, induces endothelial cytotoxicity (Zhong et al., 2002), endoplasmatic stress as well as the unfolded protein response (Zhou et al., 2005), and increases ROS production, whereas NO levels are decreased (Chai et al., 2005a,b; Conklin et al., 2004), leading to inhibition of NO-mediated vasorelaxation (reviewed in Wang et al., 2007). In addition to these cellular effects, animal and cell culture experiments indicate that CD36 over-expression induced by treatment with ARPI is centrally involved in increasing the premature risk for atherosclerosis (Dressman et al., 2003). Depending on the experimental system used, the mechanisms of CD36 over-expression by ritonavir involves protein kinase C (PKC) (Bradshaw et al., 2006; Dressman et al., 2003), the estrogen receptor alpha (ERa) (Allred et al., 2006), as well as cellular proteasome inhibition in human THP-1 monocytes (Munteanu et al., 2004a, 2005). In ritonavir-treated mouse macrophages, PKC activation and increased PPARc and CD36 expression are reverted by the nucleoside reverse transcriptase inhibitor didanosine via increased ubiquitination and degradation of PKCa, whereas a-tocopherol is without effect in this in vivo model (Bradshaw et al., 2006; Dressman et al., 2003). In THP-1 monocytes, a-tocopherol interferes with proteasome inhibition by ritonavir and the normalization of proteasome activity may explain the reversion of ritonavir-induced CD36 scavenger receptor over-expression by a-tocopherol (Munteanu et al., 2004a; Munteanu et al., 2005). The activity of the proteasome is modulated by oxidative stress, and ritonavir increases the production of reactive oxygen species (ROS) in endothelial cells possibly via proteasome inhibition (Conklin et al., 2004; Reinheckel et al., 1998). In vivo, the proteasome is inhibited directly by oxidative modification occurring after coronary occlusion/reperfusion as well as in atherosclerotic plaques (Bulteau et al., 2001; Versari et al., 2006). It remains to be determined whether compounds with antioxidant action such as a-tocopherol normalize proteasome activity by reducing oxidative stress or by alternative mechanisms. 5.4. Molecular and cellular effects of a-tocopheryl phosphate and EPC-K1 in cells of the vascular system The phosphorylated form of a-tocopherol, a-tocopheryl phosphate, occurs naturally in foods and in animal as well as in human tissues (Gianello et al., 2005; Ogru et al., 2003). a-Tocopheryl phosphate has per se no antioxidant activity, but nevertheless reduces oxidative stress by preventing the propagation of free radicals in membranes (Rezk et al., 2004). Supplementation of the diet of rats with a-tocopheryl phosphate increases the deposition of a-tocopheryl phosphate and a-tocopherol in liver and adipose tissue, without exerting any significant toxicity in several animal models (Libinaki et al., 2005; Ogru et al., 2003). Atherosclerosis progression and CD36 scavenger receptor over-expression in hypercholesterolemic rabbits is better

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prevented by a-tocopheryl phosphate when compared to a-tocopheryl acetate (Negis et al., 2006). Similar to that, in human THP-1 monocytic leukaemia cells and rat aortic smooth muscle cells (RASMC), a-tocopheryl phosphate is more potent than atocopherol in inhibiting cell proliferation and in reducing CD36 mRNA and protein expression (Munteanu et al., 2004c), and cytotoxicity in THP-1 monocytes is only seen at high concentrations (Munteanu et al., 2004c). The higher potency of a-tocopheryl phosphate in these experiments may be due to a better uptake of the molecule and to its intracellular hydrolysis leading to higher atocopherol concentrations at sensitive sites, or to its direct interaction with specific proteins and cellular structures. Preliminary results suggest that a-tocopherol can be phosphorylated and de-phosphorylated in cell culture and animal tissues (Gianello et al., 2005; Nakayama et al., 2003; Negis et al., 2005), suggesting that interconversion may serve some cellular signalling functions. Related to a-tocopheryl phosphate is EPC-K1 (L-ascorbic acid 2-[3,4-dihydro2,5,7,8-tetramethyl-2-(4,8,12-trimethytridecyl)-2H-1-benzopyran-6-yl-hydrogenphosphate] potassium salt), a composite molecule between vitamin E (a-tocopherol) and vitamin C (L-ascorbate), linked by a phosphodiester bond. It is unknown to what degree EPC-K1 is cleaved by enzymes in vivo; however, in vitro stability studies suggest that some a-tocopheryl phosphate is produced as a hydrolytic decomposition product (Ohba et al., 1994). EPC-K1 acts via its enolic hydroxyl group as a potent scavenger for both hydrophilic and hydrophobic radicals, including hydroxyl radicals, superoxide, peroxynitrites, as well as alkyl and lipid radicals (Wei et al., 1999b). In addition to that, EPCK1 is chelating Cu2+ and Fe2+ thus reducing free radicals generation via the Fenton reaction (Tomita et al., 2000). In several studies EPC-K1 was able to protect against ischemia-reperfusion injury during transplantation or vessel occlusion, e.g. in muscle (Hirose et al., 1997), lung (Nagahiro et al., 1997), liver (Yagi et al., 1997, 1992), brain (Kato et al., 2003), and during myocardial infarction (Kuribayashi et al., 1996; Yamada et al., 1998a). NOinduced neurotoxicity is reduced by EPC-K1 by preventing apoptosis and mitochondrial dysfunction in cerebellar granule cells (Wei et al., 1999a). EPC-K1 furthermore modulates NF-jB and the glucocorticoid receptor via redox regulation (Hirano et al., 1998; Okamoto et al., 1998), inhibits phospholipase A2 activity and stimulates endothelial nitric oxide production leading to endothelium-dependent relaxation (Takayama et al., 2003). EPC-K1 has not been tested as a preventive agent against atherosclerosis, although combinatorial treatment with vitamin E and C was more potent in several studies, possibly as a result of regeneration of vitamin E by vitamin C (Abudu et al., 2004; Antoniades et al., 2003; Chan, 1993; May, 1999).

6. Conclusions Animal studies clearly show preventive action of vitamin E against atherosclerosis in many experimental settings, which can be explained by the molecular and cellular

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effects of vitamin E seen in cell culture studies. The situation in humans is less clear; whereas several smaller epidemiological studies supported an anti-atherosclerotic role of vitamin E, recent meta-analyses of clinical trials reported neutral or even negative effects of vitamin E supplementation against cardiovascular disease, in particular in patients with often advanced disease symptoms and undocumented plasma vitamin E levels. Thus the situation in humans is more complex and probably less controllable than in animals or cell culture. Nevertheless, clearer effects of vitamin E supplementation are seen in vitamin E deficient animals, and it is likely that similar statements can be made in humans. Vitamin E deficiency as a consequence of nutritional deficits is rare in humans, but can occur systemically due to several lipid malabsortion syndromes, as a consequence of mutations of the a-tocopherol transfer protein (a-TTP) leading to the congenital recessive neurological disease called ataxia with vitamin E deficiency (AVED), or possibly locally as a result of vitamin E consumption due to increased oxidative stress associated with several diseases. In addition to that, several proteins have recently been discovered to be involved in vitamin E absorption, distribution, transport, metabolisms and excretion, and mutations or polymorphisms in these genes could generate further deficiency syndromes with possible influence on atherosclerotic events.

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