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Cardiovascular Research 2001 51(2):198-201; doi:10.1016/S0008-6363(01)00353-4
© 2001 by European Society of Cardiology
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Copyright © 2000, European Society of Cardiology

Effects of vitamin E on the endothelium: equivocal? {alpha}-tocopherol and endothelial dysfunction

Francesco Visioli*

Department of Pharmacological Sciences, University of Milan, Via Balzaretti 9, 2013 Milan, Italy

* Tel.: +39-02-5835-8280; fax: +39-02-7004-26106 francesco.visioli{at}unimi.it

Received 22 May 2001; accepted 29 May 2001

See article by Bauersachs et al. [5] (pages 344–350) in this issue.


   1. Introduction
Top
 1. Introduction
2. Do we need...
 3. Which strategy should...
 4. Are we carrying...
 5. Conclusion
 References
 
‘Endothelial dysfunction’ refers to a common complication of atherosclerosis, when impaired vasorelaxation due to reduced endothelial-derived nitric oxide (EDNO) bioactivity results in altered endothelial function [1,2]. In addition to atherosclerosis, evidence is accumulating of a dysfunctional endothelium and defective vasomotion in congestive heart failure patients [3–5].

Oxidative stress — the excessive production of reactive oxygen species (ROS) that overcomes antioxidant defense mechanisms in cells — plays an important role in endothelial dysfunction. Our current knowledge suggests that endothelial dysfunction is due to either (or both) a reduced production of EDNO or to its accelerated reaction with other species, notably ROS, of which the superoxide anion is the most widely studied [6]. Thus far, the three most widely studied sources of vascular ROS are reactions catalyzed by xantine oxidoreductase, NADH/NADPH oxidase, and NO synthase (NOS) [7,8].


   2. Do we need more NO? No!
Top
 1. Introduction
 2. Do we need...
3. Which strategy should...
 4. Are we carrying...
 5. Conclusion
 References
 
...well, at least not always. For example, the high reaction rate between superoxide and EDNO (6.7x109 mol l–1 s–1) is about three times faster than that between superoxide and superoxide dismutase (SOD); as a result, EDNO can outcompete SOD and act as a stronger antioxidant than the latter. Alas, the scavenging of superoxide by EDNO does not lower its potential of generating oxidative stress: the formation of peroxynitrite (the ‘ugly’ side of nitric oxide [9]) that follows this reaction, and the subsequent reaction of peroxynitrite with carbon dioxide, to form a highly reactive nitrosoperoxocarbonate intermediate [10], is likely to be more detrimental, in terms of oxidant flux, than the generation of superoxide per se [11]. Finally, we should not overlook the fact that EDNO can rapidly react with oxygen to start a chain of reactions that leads to the formation of a series of highly reactive nitrogen/oxygen species, e.g. nitrogen dioxide [10,12]: the presence of 3-nitrotyrosine in tissues is an index of nitrosative stress [12] and reveals the formation and activity of such reactive nitrogen species [13]. Hence, under certain circumstances, the generation of superoxide may play a protective role, as it ‘disposes of excess NO·, in order to maintain the correct balance between these radicals in vivo’ [13]. In turn, this prooxidant-versus-antioxidant outcome depends on relative concentrations of individual reactive species [14].

Interestingly, inhibition of nitric oxide synthase prevents cardiac ischemia/reperfusion damage [15]. This effect may be a consequence of both a reduced formation of reactive nitrogen species and the prevention of NOS uncoupling. NOS uncoupling [7,8] is a consequence of a reduced availability of either substrate (i.e. L-arginine [16,17]) or cofactor (i.e. tetrahydrobiopterin [17,18]). Under these circumstances, NOS starts to produce superoxide and hydrogen peroxide, leading to both lower net concentrations of EDNO and to the potential production of peroxynitrite [7]. In turn, overstimulation of NOS activity in the absence of an adequate environment may be detrimental and leads to an excessive superoxide flux.


   3. Which strategy should we choose?
Top
 1. Introduction
 2. Do we need...
 3. Which strategy should...
4. Are we carrying...
 5. Conclusion
 References
 
It is noteworthy that vitamin E is a weak scavenger of superoxide (k2=4.9x103 mol l–1 s–1) [19]. It is likely that the observed reduction of superoxide-dependent oxidative stress following antioxidant, i.e. vitamin E, supplementation is due to a lower generation of this radical [20] rather than to an increased removal. Likewise, studies of the effects of vitamin C on endothelial dysfunction pointed out that, due to the slow rate of reaction between superoxide and vitamin C, ascorbic acid exerts a direct tonic activity on EDNO production rather than a scavenging activity on superoxide [8,21]. It is clear that agents aimed at ameliorating oxidative stress-dependent endothelial dysfunction should be assessed by their effectiveness to promote (or restore) proper EDNO production by the arterial wall.

In addition to restoring a proper EDNO production, we should render it more bioavailable by reducing superoxide concentrations. However, the use of SOD as a therapeutic tool to reduce oxidant flux and ameliorate endothelial dysfunction has several limitations. For example, SOD does not cross the blood–brain barrier and does not penetrate cells; further, it is highly susceptible to proteolytic digestion upon administration [22]. To overcome these limitations, stable SOD mimics are being studied [22–24]. Still at an early stage of clinical study, these stable analogs may prove useful in the therapy of oxidant-mediated injury.


The evasive evaluation of E

Currently, there is a bit of confusion concerning the activities of the different isoforms of vitamin E as well as their source, either natural or synthetic. The term ‘vitamin E’ includes eight compounds, four tocopherols and four tocotrienols, which share vitamin E activity. Yet, by definition, only {alpha}-tocopherol contributes to the RDA value [26], because the other naturally occurring isoforms (β, {gamma}, and {delta} tocopherols and the tocotrienols) are not converted to {alpha}-tocopherol by humans and act as poor substrates for the liver {alpha}-tocopherol transfer protein. This fact is particularly important because most nutrient databases and food labels do not distinguish between different tocopherols in food. Further, the only stereoisoforms of {alpha}-tocopherol that are maintained in human plasma are the naturally occurring form (RRR-) and the three synthetic 2R-stereoisomers (RSR-, RRS-, and RSS-).

From a clinical point of view, it should be noted that the synthetic {alpha}-tocopherol often employed in clinical studies is all racemic (all rac, often incorrectly termed dl-{alpha}-tocopherol), although a portion of it is not maintained in human plasma and tissues [39,40]. Hence, the bioactivity of natural {alpha}-tocopherol (which is also more bioavailable than the synthetic form) should be expected to be twice that of the synthetic formulation [39].

Another matter of confusion arises from the nonuniform use of either international units (IU) or milligrams to express doses of vitamin E. In 1980, the United States Pharmacopeia changed IU to USP units, although the former definition is still in use by food and supplement companies. One USP (or IU) is defined as having the activity of 1 mg of all-rac-{alpha}-tocopheryl acetate, 0.67 mg RRR-{alpha}-tocopherol, or 0.74 mg RRR-{alpha}-tocopheryl acetate. To compare the results of clinical studies with dietary habits, it is convenient to convert IU to mg by employing the following formulas:


Formula


Formula

 


   4. Are we carrying out biologically relevant experiments?
Top
 1. Introduction
 2. Do we need...
 3. Which strategy should...
 4. Are we carrying...
5. Conclusion
 References
 
A major limitation of most studies of {alpha}-tocopherol carried out in laboratory animals, including that of Bauersachs et al. [5], is the enormous amount of tocopherols (and tocotrienols) contained in the rat chow, which may affect the outcomes of experiments using this animal model [25]. These compounds are usually added to increase both the shelf-life of the chow and the fertility and health of animals [25]. In addition, most investigators usually do not consider the amount of vitamin E consumed by human subjects when they design experimental protocols. For example, if the design of the Bauersachs study was to be transposed to humans, an impractical daily intake of 14 g (for a 70-kg human being) would be necessary to observe the same effects. This intake is (i) almost 1000 times higher than the current RDA of 15 mg of {alpha}-tocopherol/day for adult men and women ages 19 and older [26] and (ii) much higher than the average intake of {alpha}-tocopherol from food in the US, which is ~9 mg daily for men and 6 mg daily for women [27]. Admittedly, the RDA for vitamin E is based on the prevention of deficiency symptoms rather than on health promotion and the prevention of chronic disease [27], but the effects of large vitamin E supplementation on certain cardiovascular diseases are far from being established [28,29]. Further, Keaney et al. demonstrated that supplementation of cholesterol-fed rabbits with high vitamin E doses leads to impaired vasodilator function and even increases intimal proliferation [30]. In addition, demonstration of a tocopherol-mediated peroxidation [31,32], suggests caution when employing high supplemental doses of tocopherols. Thus, it is conceivable that an extremely high load of vitamins, including {alpha}-tocopherol, might favor lipid peroxidation, unfavorably alter the optimal cellular redox state, and negatively interfere with certain enzymatic activities. Finally, a dramatic dietary increase of vitamin E consumption would lead to a concomitant increase in total fat intake, well above the recommended 30% of total calories.

The effects of antioxidants, including vitamins, on cell function are multi-faceted and extend beyond their antioxidant activities. Interested readers are invited to peruse a Focused Issue of Cardiovascular Research dedicated to ‘Antioxidants in the Cardiovascular System’ [33]. Relevant to the subject of this editorial, it has been proposed that {alpha}-tocopherol-mediated endothelial cell muscarinic receptors phosphorylation by PKC may result in increased NOS activation by various agonists [34].


   5. Conclusion
Top
 1. Introduction
 2. Do we need...
 3. Which strategy should...
 4. Are we carrying...
 5. Conclusion
References
 
While there is now considerable evidence of beneficial effects of vitamin C supplementation on endothelial function [21], the data on vitamin E are still scant and conflicting (Table 1). The rationale supporting the administration of vitamin E to healthy individuals has been questioned, because vitamin E supplementation does not affect markers of oxidative stress [35]. Thus, indiscriminate administration to humans, including healthy individuals and subjects at risk of oxidative stress (‘the rancids’ [36]) may be equivocal and, in clinical studies, this strategy might obscure a true population susceptible to benefit from supplementation [35]. To move forward with studies of antioxidant supplementation on vascular dysfunction, future investigations should employ realistic doses of {alpha}-tocopherol, should adopt reliable markers of in vivo oxidative stress (which are still insufficient at present [36–38]), and should try to discriminate among the interactions of vitamin E with the different reactive species generated within the vascular wall.


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  		Table 1 Human studies of vitamin E and endothelial function

 


   Acknowledgements
 
Dr. John P. Doucet, an Acadian molecular biologist and playwright, edited the manuscript and chose the title. The author had fruitful discussions on this topic with Drs. Balz Frei and Tory Hagen from the Linus Pauling Institute, Oregon State University.


   References
Top
 1. Introduction
 2. Do we need...
 3. Which strategy should...
 4. Are we carrying...
 5. Conclusion
 References
 

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