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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2002;22:861.)
© 2002 American Heart Association, Inc.

Thrombosis

PAR-4 Agonist AYPGKF Stimulates Thromboxane Production by Human Platelets

Ruth Ann Henriksen; Vallere K. Hanks

From the Department of Internal Medicine, Brody School of Medicine at East Carolina University, Greenville, NC.

Correspondence to Ruth Ann Henriksen, Division of Allergy, Immunology and Rheumatology, Department of Internal Medicine, East Carolina University, 600 Moye Blvd, Greenville NC 27858-4354. E-mail henriksenr@ mail.ecu.edu

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 µmol/L AYPGKF. Thromboxane produced by the combined stimulation of PAR-1 and PAR-4 is additive. Pretreatment of platelets with 45 µmol/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 µmol/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.

Key Words: thromboxane • platelets • thrombin • PAR-1 • PAR-4

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