KRDS, a peptide derived from human lactotransferrin, inhibits thrombin-induced thromboxane synthesis by a cyclooxygenase-independent mechanism.
KRDS, a tetrapeptide from human lactotransferrin, inhibits thrombin-induced platelet aggregation, secretion and thromboxane (TX) synthesis without interfering with phospholipase C (PLC) beta activation, since in previous work we have shown that Ca2+ mobilization and phosphorylation of the myosin light chain kinase (20 kDa) and pleckstrin (47 kDa) were normal. However, the inhibition of arachidonic acid-induced aggregation in the presence of KRDS is accompanied by normal TX synthesis suggesting that it does not interfere with the cyclooxygenase activity. To elucidate further the mechanisms of action of this peptide we tested its effect on U46619-induced platelet activation. KRDS inhibits U46619-induced platelet aggregation time- and dose-dependently without inhibiting the phosphorylation of pleckstrin. This suggests that the PLC pathway is not affected and that the inhibitory effect of KRDS is not due to and uncoupling of TXA2 from its receptor. In addition to the PLC pathway, protein tyrosine kinases play a major role in platelet signal transduction mechanisms. At least 7 tyrosine-phosphorylated proteins are detected upon stimulation of platelets by thrombin. KRDS strongly inhibits the tyrosine-phosphorylated substrates, in particular two 100-105 kDa substrates which are related to GP IIb/IIIa activation and platelet aggregation. The absence of TX synthesis observed in the presence of KRDS could be due to the inactivation of cPLA2 since the latter needs tyrosine phosphorylation to be activated, thus explaining the inhibitory action of KRDS on platelet functions.
D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D000595:Amino Acid Sequence; D000818:Animals; D016718:Arachidonic Acid / Q000494:pharmacology; D001798:Blood Proteins / Q000378:metabolism; D002417:Cattle; D003864:Depression, Chemical; D006801:Humans; D007781:Lactoferrin / Q000737:chemistry* / Q000302:isolation & purification / Q000494:pharmacology*; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000302:isolation & purification / Q000494:pharmacology*; D010750:Phosphoproteins; D010766:Phosphorylation / Q000187:drug effects; D015539:Platelet Activation / Q000187:drug effects; D010975:Platelet Aggregation Inhibitors / Q000302:isolation & purification / Q000494:pharmacology*; D011450:Prostaglandin Endoperoxides, Synthetic / Q000037:antagonists & inhibitors / Q000494:pharmacology; D011451:Prostaglandin-Endoperoxide Synthases; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013917:Thrombin / Q000037:antagonists & inhibitors*; D013928:Thromboxane A2 / Q000031:analogs & derivatives / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000494:pharmacology
D001798:Blood Proteins; D010446:Peptide Fragments; D010750:Phosphoproteins; D010975:Platelet Aggregation Inhibitors; D011450:Prostaglandin Endoperoxides, Synthetic; C039077:platelet protein P47; C056549:KRDS peptide; D016718:Arachidonic Acid; D013928:Thromboxane A2; D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D011451:Prostaglandin-Endoperoxide Synthases; D011505:Protein-Tyrosine Kinases; D007781:Lactoferrin; D013917:Thrombin