Different isoforms of tocopherols enhance nitric oxide synthase phosphorylation and inhibit human platelet aggregation and lipid peroxidation: implications in therapy with vitamin E.
BACKGROUND
alpha-Tocopherol has received much attention in the primary and secondary prevention of coronary artery disease. Absence of other isoforms, such as gamma- and delta-tocopherol, in commercial preparations of vitamin E may account for the inconsistent results of clinical trials. Since platelet aggregation is intimately involved in thrombogenesis, the relative effects of alpha-, gamma-, and delta-tocopherol and their combination were examined on human platelet aggregation, lipid peroxidation, and constitutive nitric oxide synthase (cNOS) activity.


RESULTS
Human platelets were incubated with the three different isoforms of tocopherol and their combination for 30 minutes, and then ADP-induced platelet aggregation measured. All three isoforms of tocopherol markedly and similarly decreased platelet aggregation in a concentration (120--480 microM)-dependent manner. All three tocopherols also decreased the level of the lipid peroxidation product, malondialdehyde (MDA), and increased NO release (P < 0.05 vs control). These isoforms of tocopherol did not affect cNOS protein expression, but enhanced cNOS phosphorylation in platelets. The combination of three tocopherols in a concentration found in nature was more potent than alpha-, gamma-, or delta-tocopherol alone in this regard.


CONCLUSIONS
These observations suggest that all three major isoforms of tocopherol have a similar effect on human platelet aggregation. The three isoforms appear to attenuate platelet aggregation at least in part via a decrease in free radical generation and an increase in platelet cNOS activity. The combination of tocopherols has a synergistic platelet inhibitory effect. Future clinical trials should concentrate on the combination of these three isoforms of tocopherols.
Li
D
D
Department of Medicine, University of Florida and VA Medical Center, Gainesville, USA.
Saldeen
T
T
Romeo
F
F
Mehta
J L
JL
D000704:Analysis of Variance; D001792:Blood Platelets / Q000378:metabolism; D005227:Fatty Acids / Q000494:pharmacology; D006801:Humans; D066298:In Vitro Techniques; D015227:Lipid Peroxidation / Q000187:drug effects*; D009569:Nitric Oxide / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000378:metabolism*; D052250:Nitric Oxide Synthase Type III; D010766:Phosphorylation / Q000187:drug effects; D010974:Platelet Aggregation / Q000187:drug effects*; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology; D020033:Protein Isoforms / Q000494:pharmacology; D014810:Vitamin E / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use
D005227:Fatty Acids; D010975:Platelet Aggregation Inhibitors; D020033:Protein Isoforms; C013584:lipid peroxidation inhibitor; D014810:Vitamin E; D009569:Nitric Oxide; C496314:NOS3 protein, human; D019001:Nitric Oxide Synthase; D052250:Nitric Oxide Synthase Type III