Low concentrations of lipid hydroperoxides prime human platelet aggregation specifically via cyclo-oxygenase activation.
There is mounting evidence that lipid peroxides contribute to pathophysiological processes and can modulate cellular functions. The aim of the present study was to investigate the effects of lipid hydroperoxides on platelet aggregation and arachidonic acid (AA) metabolism. Human platelets, isolated from plasma, were incubated with subthreshold (i.e. non-aggregating) concentrations of AA in the absence or presence of hydroperoxyeicosatetraenoic acids (HPETEs). Although HPETEs alone had no effect on platelet function, HPETEs induced the aggregation of platelets co-incubated with non-aggregating concentrations of AA, HPETEs being more potent than non-eicosanoid peroxides. The priming effect of HPETEs on platelet aggregation was associated with an increased formation of cyclo-oxygenase metabolites, in particular thromboxane A2, and was abolished by aspirin, suggesting an activation of cyclo-oxygenase by HPETEs. It was not receptor-mediated because the 12-HPETE-induced enhancement of AA metabolism was sustained in the presence of SQ29, 548 or RGDS, which blocked the aggregation. These results indicate that physiologically relevant concentrations of HPETEs potentiate platelet aggregation, which appears to be mediated via a stimulation of cyclo-oxygenase activity.
Calzada
C
C
INSERM U 352 (affiliated to CNRS), Biochimie et Pharmacologie, INSA-Lyon, Bâtiment 406, 20 Avenue Albert Einstein, 69621 Villeurbanne, France.
Vericel
E
E
Lagarde
M
M
D019377:12-Hydroxy-5,8,10,14-eicosatetraenoic Acid / Q000378:metabolism; D016718:Arachidonic Acid / Q000378:metabolism; D001241:Aspirin / Q000494:pharmacology; D001792:Blood Platelets / Q000187:drug effects* / Q000201:enzymology; D019086:Bridged Bicyclo Compounds, Heterocyclic; D003676:Deferoxamine / Q000494:pharmacology; D004789:Enzyme Activation; D005231:Fatty Acids, Unsaturated / Q000378:metabolism; D006801:Humans; D006834:Hydrazines / Q000494:pharmacology; D006861:Hydrogen Peroxide / Q000494:pharmacology; D015289:Leukotrienes / Q000494:pharmacology; D008054:Lipid Peroxides / Q000494:pharmacology*; D009842:Oligopeptides / Q000494:pharmacology; D010545:Peroxides / Q000494:pharmacology; D010974:Platelet Aggregation / Q000187:drug effects*; D011451:Prostaglandin-Endoperoxide Synthases / Q000097:blood*; D013929:Thromboxane B2 / Q000378:metabolism; D014810:Vitamin E / Q000494:pharmacology; D020122:tert-Butylhydroperoxide
D019086:Bridged Bicyclo Compounds, Heterocyclic; D005231:Fatty Acids, Unsaturated; D006834:Hydrazines; D015289:Leukotrienes; D008054:Lipid Peroxides; D009842:Oligopeptides; D010545:Peroxides; D014810:Vitamin E; D016718:Arachidonic Acid; C008033:12-hydroxy-5,8,10-heptadecatrienoic acid; D013929:Thromboxane B2; D019377:12-Hydroxy-5,8,10,14-eicosatetraenoic Acid; C021201:12-HPETE; C025086:15-hydroperoxy-5,8,11,13-eicosatetraenoic acid; C045749:SQ 29548; D020122:tert-Butylhydroperoxide; C046617:arginyl-glycyl-aspartyl-serine; D006861:Hydrogen Peroxide; D011451:Prostaglandin-Endoperoxide Synthases; D003676:Deferoxamine; D001241:Aspirin