Sphingosylphosphorylcholine, a naturally occurring lipid mediator, inhibits human platelet function.
1 The lysophospholipids, lysophosphatidic acid and sphingosine 1-phosphate, have been reported to activate platelets. Here we examined effects of the naturally occurring related sphingosylphosphorylcholine (SPC) on human platelet function. 2 Platelet activation was determined as aggregation, elevation of intracellular Ca(2+) concentrations, surface expression of P-selectin, GP 53, and GP IIb/IIIa neoepitope PAC-1, and of fibrinogen binding to the platelet surface. 3 Platelets were activated by ADP (5 and 20 micro M), the thrombin receptor-activating peptide TRAP-6 (5 and 20 micro M), the thromboxane A(2) mimetic U-46619 (1 micro M) and collagen (20 and 50 micro g ml(-1)) but not by SPC (up to 20 micro M). 4 SPC concentration-dependently (IC(50) approximately 1-10 micro M) inhibited activation of washed human platelets in response to all of the above agonists, with almost complete inhibition occurring at 20 micro M SPC. 5 The SPC stereoisomers, D-erythro SPC and L-threo SPC, exhibited similar concentration-response curves in inhibiting 20 micro M ADP-induced platelet aggregation, suggesting that SPC did not act via specific lysophospholipid receptors. 6 Although SPC slightly activated platelet protein kinase A (as assessed by VASP phosphorylation), this effect could not explain the marked platelet inhibition. Possible protein kinase C inhibition also did not explain the inhibition of platelet activation by SPC. On the other hand, SPC suppressed agonist-induced Ca(2+) mobilization and phospholipase C stimulation. 7 These results indicate that the lysophospholipid SPC is an effective inhibitor of human platelet activation, apparently primarily by uncoupling agonist-activated receptors from their effectors.
Altmann
Christoph
C
Institut für Pharmakologie, Universitätsklinikum Essen, Germany.
Meyer Zu Heringdorf
Dagmar
D
Böyükbas
Dilek
D
Haude
Michael
M
Jakobs
Karl H
KH
Michel
Martin C
MC
D001792:Blood Platelets / Q000187:drug effects* / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005434:Flow Cytometry; D006801:Humans; D066298:In Vitro Techniques; D010767:Phosphorylcholine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology*; D010974:Platelet Aggregation / Q000187:drug effects*; D010975:Platelet Aggregation Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism; D013110:Sphingosine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology*; D013997:Time Factors; D010738:Type C Phospholipases / Q000378:metabolism
D010975:Platelet Aggregation Inhibitors; C005356:sphingosine phosphorylcholine; D010767:Phosphorylcholine; D017868:Cyclic AMP-Dependent Protein Kinases; D011493:Protein Kinase C; D010738:Type C Phospholipases; D013110:Sphingosine; D002118:Calcium