title: alpha-tocopherol inhibits aggregation of human platelets by a protein kinase C-dependent mechanism.
abstract: BACKGROUND
  Epidemiological studies indicate that vitamin E (alpha-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.
  
  
  RESULTS
  Using gel-filtered platelets derived from platelet-rich plasma treated with alpha-tocopherol (500 mumol/L) or vehicle (0.5% ethanol), we found that inhibition of platelet aggregation by alpha-tocopherol was closely linked to its incorporation into platelets (r = -.78; P < .02). Platelet incorporation of alpha-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 alpha-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 alpha-tocopherol (400 to 1200 IU/d) resulted in an increase in platelet alpha-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 alpha-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 alpha-tocopherol in preventing the development of coronary artery disease.
authors.affiliation: Whitaker Cardiovascular Institute, Boston University School of Medicine, MA 02118-2394, USA.
authors.forename: J E
authors.initials: JE
authors.lastname: Freedman
authors.forename: J H
authors.initials: JH
authors.lastname: Farhat
authors.forename: J
authors.initials: J
authors.lastname: Loscalzo
authors.forename: J F
authors.initials: JF
authors.lastname: Keaney
mesh_terms: D001792:Blood Platelets / Q000378:metabolism; D006801:Humans; D010974:Platelet Aggregation / Q000187:drug effects*; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology*; D011493:Protein Kinase C / Q000502:physiology*; D014810:Vitamin E / Q000097:blood / Q000494:pharmacology*
chemical_list: D010975:Platelet Aggregation Inhibitors; D014810:Vitamin E; D011493:Protein Kinase C