alpha-Tocopherol and protein kinase C inhibition enhance platelet-derived nitric oxide release.
Platelet activation is tightly regulated by products of the endothelium and platelets including nitric oxide (NO). Excess vascular oxidative stress has been associated with impaired NO release, and antioxidant status has been shown to alter endothelium-derived NO bioactivity. Although physiological levels of a-tocopherol are known to inhibit platelet function, the effect of a-tocopherol on platelet NO release is unknown. Loading platelets with physiologic levels of a-tocopherol increased platelet NO production approximately 1.5-fold (Pa-tocopherol, platelet NO release increased 50% (Pa-Tocopherol-loaded platelets also produced 74% less superoxide as compared with control (Pa-tocopherol inhibited PKC-dependent eNOS phosphorylation as determined by immunoprecipitation. Lastly, platelets isolated from NOS3-deficient mice released 80% less superoxide as compared with control animals (P=0.011), and incubation of NOS III-deficient platelets with 500 mM a-tocopherol only caused a modest additional decrease in platelet superoxide release (NS). Thus, a-tocopherol appears to enhance platelet NO release both in vitro and in vivo through antioxidant- and PKC-dependent mechanisms.
Freedman
J E
JE
Department of Pharmacology, Georgetown University Medical Center, Washington, D.C. 20007, USA. Freedmaj@gunet.georgetown.edu
Li
L
L
Sauter
R
R
Keaney JF
J R
JR
D000470:Alkaloids; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D053119:Benzophenanthridines; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D051379:Mice; D008817:Mice, Mutant Strains; D008954:Models, Biological; D009569:Nitric Oxide / Q000378:metabolism*; D019001:Nitric Oxide Synthase / Q000172:deficiency / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; D010617:Phenanthridines / Q000494:pharmacology; D010766:Phosphorylation; D015539:Platelet Activation / Q000187:drug effects / Q000502:physiology*; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology; D011493:Protein Kinase C / Q000037:antagonists & inhibitors*; D013481:Superoxides / Q000378:metabolism; D014810:Vitamin E / Q000494:pharmacology*
D000470:Alkaloids; D000975:Antioxidants; D053119:Benzophenanthridines; D004791:Enzyme Inhibitors; D010617:Phenanthridines; D010975:Platelet Aggregation Inhibitors; D013481:Superoxides; D014810:Vitamin E; D009569:Nitric Oxide; C016299:chelerythrine; C496314:NOS3 protein, human; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; C496315:Nos3 protein, mouse; D011493:Protein Kinase C