Elsevier

Atherosclerosis

Volume 147, Issue 1, November 1999, Pages 177-185
Atherosclerosis

Moderate supplementation with natural α-tocopherol decreases platelet aggregation and low-density lipoprotein oxidation

https://doi.org/10.1016/S0021-9150(99)00169-0Get rights and content

Abstract

Previous studies have shown that oral administration of 300 mg α-tocopherol/day to healthy volunteers decreases platelet function and enhances their sensitivity to the platelet inhibitor, prostaglandin E1, when full dose-response curves to a range of agonist concentrations are made. In this study, the effects of oral doses of natural α-tocopherol (75, 200 and 400 IU/day) were studied in order to determine whether the same effects might be achieved with lower intakes of vitamin E and whether inhibition is related to the platelet levels of the antioxidant in platelet membranes. Twenty two subjects undertook the supplementation regime, divided into three units of 2 weeks, each cycling through each of the dosages. The results show that uptake of vitamin E by the platelets was optimal at 75 IU/day, correlating with the maximal influence on platelet aggregation and platelet responsiveness to inhibition by PGE1, increased supplemental levels exerting no greater effects.

Introduction

The hyperactivity of blood platelets [1], [2] and elevated plasma levels of low-density lipoproteins (LDL) are recognised risk factors for cardiovascular disease. In recent years, it has also been recognised that the oxidation of these lipoproteins in the artery wall may be an important factor in the aetiology of atherogenesis [3]. Patients with verifiable coronary atherosclerosis have LDL which show increased susceptibility to oxidation in vitro [4]. This relationship may be due, in part, to the cytotoxicity of the products of lipid oxidation on the arterial cells, including the endothelium [3]. The effects of lipoprotein oxidation and its products include a decrease in the release of nitric oxide [5] and the possibility of prostacyclin [6]. Lipoproteins also have direct effects on platelets [7]. Hyperchlolesterolaemia may enhance the activation of platelets, but this may in part be due to increased concentrations of cholesterol in their membranes. However, only mild oxidation of LDL enhances the activation of platelets [8], [9] which may be attributed to increased concentrations of lipid peroxides [10] known to activate thromboxane biosynthesis [11].

Vitamin E, an antioxidant vitamin found in membrane of platelets, as in other cells, is carried in the plasma at high concentrations in LDL. There is accumulating evidence to support a link between dietary vitamin E and a reduced incidence of atherosclerosis [12], [13], [14], [15], [16], [17], [18], [19]. Raising the vitamin E concentration of LDL in vitro increases the resistance to oxidation of LDL by cupric ions [20] as do dietary supplements of the vitamin [21], [22], [23].

Vitamin E may also exert its action at cellular level by reducing membrane fluidity [24] or by reducing the oxidation of membrane lipids. In platelets, vitamin E inhibits platelet activation in vitro [25], [26], [27] as well as granular release reactions [24] and platelet adhesion [28], [29]. However, in vivo the effectiveness of vitamin E as an anti-aggregatory agent has been less well-accepted [25], [30], [31]. In a study of men with low antioxidant status, Salonen showed that the measurement of high platelet activation and secretion of platelets products in this group was associated with high concentration of plasma lipid peroxides [32] and could be reversed with a cocktail of antioxidants. In recent work by the authors of this study, it was shown clearly that the oral administration of 300 mg α-tocopherol per day to healthy adults also decreased platelet aggregation ex vivo and enhanced their sensitivity to the platelet inhibitor prostaglandin E1 when full dose response curves to a range of agonist concentrations were made [33]. A lesser effect was noted with vitamin C but no effects were found with oral β-carotene. The largest changes were observed when ADP was used as the platelet agonist.

In the current study, the effects of a range of oral doses of α-tocopherol were investigated in order to determine whether lower intakes of the vitamin (down to 75 IU/day), closer to that of the recommended dietary intake, could have similar effects. In addition to the measurement of platelet activation parameters in response to activation with ADP and the inhibition by PGE1, the effect of the oral vitamin E was measured on the resistance of LDL to oxidation ex vivo and on the concentrations of α-tocopherol in plasma, LDL and platelet membranes. The effects of the vitamin were detectable at even the lowest levels of dietary supplement tested.

Section snippets

Subjects

Ethical permission was obtained from the Lewisham and North Southwark Committee on Ethical Practice. Twenty-four healthy subjects (10 male and 14 female) were recruited with informed consent. Two volunteers (female) were withdrawn from the study because of ingestion of interfering drugs before blood sampling. All 22 remaining volunteers completed the study and compliance was very good (>99%) as assessed by the number of pills returned. The volunteers were aged between 23 and 50 years (30±5.7

Plasma lipids and lipoproteins

Plasma concentrations of cholesterol, triglycerides, HDL and LDL over the 6 weeks of supplementation with vitamin E showed no significant changes in relation to levels prior to supplementation (Table 1). With the exception of two volunteers who had cholesterol concentrations of 6.95 and 7.59 mM, all the subjects had a cholesterol level in the normal range (3–6.5 mmol/l), the mean value being 5.19±1.02 mM.

Plasma

The baseline plasma concentrations of vitamin E (Table 1) were in the normal range (mean

Discussion

Growing evidence from a number of epidemiological studies described an association between intake levels of vitamin E and a lower risk of coronary heart disease [43], [44], [14], [15] and progression of the disease [19]. Most of the studies have shown previously that the administration of high, pharmacological doses of vitamin E elevate the α-tocopherol content in LDL and prolong the lag phase to oxidation [23], [45], [46], [47]. With similar doses, vitamin E has been shown to increase the

Acknowledgements

The auhtors thank the Ministry of Agriculture, Fisheries and Food for financial support for this project (Grant CSA2403) and Henkel for supplying the natural vitamin E supplement.

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