The role of PAR4 in thrombin-induced thromboxane production in human platelets

Chin-Chung Wu; Tsong-Long Hwang; Chang-Hui Liao; Sheng-Chu Kuo; Fang-Yu Lee; Che-Ming Teng

doi:10.1160/TH03-02-0103

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 2003; 90(02): 299-316
DOI: 10.1160/TH03-02-0103

Platelets and Blood Cells

Schattauer GmbH

The role of PAR4 in thrombin-induced thromboxane production in human platelets

Chin-Chung Wu

¹Graduate Institute of Natural Products, Kaohsiung Medical University, Kaohsiung,

,

Tsong-Long Hwang

²Graduate Institute of Natural Products, College of Medicine, Chang Gung University, Taoyuan

,

Chang-Hui Liao

²Graduate Institute of Natural Products, College of Medicine, Chang Gung University, Taoyuan

,

Sheng-Chu Kuo

³Graduate Institute of Pharmaceutical Chemistry, China Medical College, Taichung,

,

Fang-Yu Lee

⁴Yung-Shin Pharmaceutical Industry Co. Ltd, Taichung

,

Che-Ming Teng

⁵Pharmacological Institute, College of Medicine, National Taiwan University, Taipei, Taiwan

› Author Affiliations

Abstract

Summary

There are two protease-activated receptors (PARs), PAR1 and PAR4, in human platelets. It has been suggested that PAR1 mediates platelet responses to low concentrations of thrombin, whereas PAR4 mediates signaling only at high concentrations. In the present study, we used a selective PAR4 blocker, YD-3, to investigate the role of PAR4 in thrombin-induced thromboxane formation in human platelets. YD-3 completely prevented thromboxane production by either a low concentration of thrombin (0.1 U/ml) or the PAR4 agonist peptide GYPGKF. In contrast, YD-3 did not affect thromboxane production caused by the PAR1 agonist peptide SFLLRN, collagen or arachidonic acid. YD-3 also decreased [³H]arachidonic acid release from thrombin-stimulated platelets. Moreover, desensitization of platelets with GYPGKF prevented low thrombin-induced thromboxane formation. The decreased thromboxane production by YD-3 is linked to inhibition of calcium influx in thrombin-stimulated platelets. These results suggest that PAR4 plays an important role in the regulation of thromboxane formation in platelets responding to thrombin through prolonged elevation of [Ca²⁺]_i and activation of phospholipase A₂. These data also indicate that PAR4 can be activated by relatively low concentrations of thrombin in human platelets. The selective inhibition of thrombin-induced thromboxane production by YD-3 may be of therapeutic benefit for thrombotic diseases.

Keywords

Protease-activated receptor - thrombin - thromboxane - platelets - YD-3

Full Text

References

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