Selective Inhibition of PAR4 (Protease-Activated Receptor 4)-Mediated Platelet Activation by a Synthetic Nonanticoagulant Heparin Analog

肝素 化学 血小板活化 药理学 蛋白酶 受体 血小板 蛋白酶激活受体 血小板聚集 细胞生物学 生物化学 医学 内科学 生物 凝血酶
作者
Yu‐Chuan Lin,Yen‐Chun Ko,Shang‐Cheng Hung,Ying‐Ting Lin,Jia-Hau Lee,Ju-Ying Tsai,Po-Hsiung Kung,Meng-Chun Tsai,Yih‐Fung Chen,Chin‐Chung Wu
出处
期刊:Arteriosclerosis, Thrombosis, and Vascular Biology [Ovid Technologies (Wolters Kluwer)]
卷期号:39 (4): 694-703 被引量:18
标识
DOI:10.1161/atvbaha.118.311758
摘要

Objective- PAR4 (protease-activated receptor 4), one of the thrombin receptors in human platelets, has emerged as a promising target for the treatment of arterial thrombotic disease. Previous studies implied that thrombin exosite II, known as a binding site for heparin, may be involved in thrombin-induced PAR4 activation. In the present study, a heparin octasaccharide analog containing the thrombin exosite II-binding domain of heparin was chemically synthesized and investigated for anti-PAR4 effect. Approach and Results- PAR4-mediated platelet aggregation was examined using either thrombin in the presence of a PAR1 antagonist or γ-thrombin, which selectively activates PAR4. SCH-28 specifically inhibits PAR4-mediated platelet aggregation, as well as the signaling events downstream of PAR4 in response to thrombin. Moreover, SCH-28 prevents thrombin-induced β-arrestin recruitment to PAR4 but not PAR1 in Chinese Hamster Ovary-K1 cells using a commercial enzymatic complementation assay. Compared with heparin, SCH-28 is more potent in inhibiting PAR4-mediated platelet aggregation but has no significant anticoagulant activity. In an in vitro thrombosis model, SCH-28 reduces thrombus formation under whole blood arterial flow conditions. Conclusions- SCH-28, a synthetic small-molecular and nonanticoagulant heparin analog, inhibits thrombin-induced PAR4 activation by interfering with thrombin exosite II, a mechanism of action distinct from other PAR4 inhibitors that target the receptor. The characteristics of SCH-28 provide a new strategy for targeting PAR4 with the potential for the treatment of arterial thrombosis.

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