(Circulation. 1996;94:2434-2440.)
© 1996 American Heart Association, Inc.
Articles |
-Tocopherol Inhibits Aggregation of Human Platelets by a Protein Kinase C–Dependent Mechanism
the Whitaker Cardiovascular Institute and Evans Memorial Department of Medicine, Boston (Mass) University School of Medicine.
Correspondence to Dr John F. Keaney, Jr, Whitaker Cardiovascular Institute, Room W507, Boston University School of Medicine, 80 E Concord St, Boston, MA 02118-2394. E-mail jkeaney@acs.bu.edu.
Background Epidemiological studies indicate that vitamin E (
-tocopherol) exerts a beneficial effect on cardiovascular disease. The effect of vitamin E has generally been attributed to its antioxidant activity and the antioxidant protection of LDL. Distinct from its effect on LDL, vitamin E is also known to inhibit platelet aggregation and adhesion in vitro, but the mechanism(s) responsible for these observations are not known.
Methods and Results Using gel-filtered platelets derived from platelet-rich plasma treated with -tocopherol (500 µmol/L) or vehicle (0.5% ethanol), we found that inhibition of platelet aggregation by -tocopherol was closely linked to its incorporation into platelets (r=-.78; P<.02). Platelet incorporation of -tocopherol was associated with a significant reduction in platelet sensitivity to aggregation by adenosine 5'-diphosphate, arachidonic acid, and phorbol ester (PMA) by approximately 0.15-, 2-, and 100-fold, respectively. In contrast, platelets treated similarly with butylated hydroxytoluene, another potent lipid-soluble antioxidant, did not demonstrate any change in sensitivity to these agents. Platelet incorporation of -tocopherol inhibited PMA-induced stimulation of platelet protein kinase C (PKC) as determined by phosphorylation of the 47-kD PKC substrate. In 15 normal subjects, oral supplementation with -tocopherol (400 to 1200 IU/d) resulted in an increase in platelet -tocopherol content that correlated with marked inhibition of PMA-mediated platelet aggregation (r=.67; P<.01). Platelets derived from these subjects after supplementation also demonstrated apparent complete inhibition of PKC stimulation by PMA.
Conclusions These data indicate that platelet incorporation of -tocopherol at levels attained with oral supplementation is associated with inhibition of platelet aggregation through a PKC-dependent mechanism. These observations may represent one potential mechanism for the observed beneficial effect of -tocopherol in preventing the development of coronary artery disease.
Key Words: vitamins • antioxidants • platelets • platelet aggregation inhibitors • thrombosis • coronary disease
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