PAR-4 agonist AYPGKF stimulates thromboxane production by human platelets.
Previous reports have indicated that thrombin-induced thromboxane production by human platelets occurs through two types of interaction between thrombin and the platelet surface. One of these interactions is with protease activated receptor(PAR)-1, the first identified thrombin receptor. These studies were undertaken to determine whether stimulation of PAR-4 also results in thromboxane production. The results show that treatment of washed human platelets with the PAR-4 agonist AYPGKF stimulates a maximum of 40% to 60% of the thromboxane produced by 100 nmol/L thrombin. Maximal thromboxane production requires approximately 1.0 mmol/L AYPGKF, despite the observation that maximal aggregation is produced by 45 micromol/L AYPGKF. Thromboxane produced by the combined stimulation of PAR-1 and PAR-4 is additive. Pretreatment of platelets with 45 micromol/L AYPGKF partially desensitizes thromboxane production in response to higher concentrations of AYPGKF and thrombin but not to stimulation by SFLLRN. PAR-4-induced stimulation is also significantly inhibited by 60 micromol/L genistein. It is concluded that activation through either PAR-1 or PAR-4 results in thromboxane production, but that stimulation of neither receptor alone produces thromboxane equivalent to that produced by 100 nmol/L thrombin. Thus, these findings demonstrate the presence of two pathways for thrombin-induced thromboxane production by platelets as proposed previously.
Henriksen
Ruth Ann
RA
Department of Internal Medicine, Brody School of Medicine at East Carolina University, Greenville, NC 27858-4354, USA. henriksenr@ mail.ecu.edu
Hanks
Vallere K
VK
D001792:Blood Platelets / Q000187:drug effects* / Q000378:metabolism*; D002469:Cell Separation; D020536:Enzyme Activators / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D019833:Genistein / Q000494:pharmacology; D006801:Humans; D009842:Oligopeptides / Q000494:pharmacology*; D010974:Platelet Aggregation / Q000187:drug effects / Q000502:physiology; D044463:Receptor, PAR-1; D018179:Receptors, Thrombin / Q000819:agonists* / Q000378:metabolism*; D013931:Thromboxanes / Q000037:antagonists & inhibitors / Q000096:biosynthesis*
D020536:Enzyme Activators; D004791:Enzyme Inhibitors; D009842:Oligopeptides; D044463:Receptor, PAR-1; D018179:Receptors, Thrombin; D013931:Thromboxanes; C455901:alanyl-tyrosyl-prolyl-glycyl-lysyl-phenylalanine; D019833:Genistein; C112908:protease-activated receptor 4