Oligosaccharide Blocks PAR1 (Proteinase-Activated Receptor 1)-PAR4-Mediated Platelet Activation by Binding to Thrombin Exosite II and Impairs Thrombosis

doi:10.1161/ATVBAHA.122.318085

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	Oligosaccharide Blocks PAR1 (Proteinase-Activated Receptor 1)-PAR4-Mediated Platelet Activation by Binding to Thrombin Exosite II and Impairs Thrombosis
	Li,Sujuan; Wang,Weili; Lin,Lisha; Yang,Lian; Cai,Ying; Yang,Xingzhi; Zhang,Taocui; Xiao,Chuang; Yan,Hui; Gao,Na; Zhao,Jinhua
	2023
发表期刊	ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY
ISSN	1524-4636
卷号	43 期号:2 页码:253-266
摘要	Background:Inappropriate activation and aggregation of platelets can lead to arterial thrombosis. Thrombin is the most potent platelet agonist that activates human platelets via two PARs (proteinase-activated receptors), PAR1 and PAR4. The aim is to study the activity and mechanism of an oligosaccharide HS-11 (the undecasaccharide, derived from sea cucumber Holothuria fuscopunctata) in inhibiting thrombin-mediated platelet activation and aggregation and to evaluate its antithrombotic activity. Methods:Platelet activation was analyzed by detecting CD62P/P-selectin expression using flow cytometry. The HS-11-thrombin interaction and the binding site were studied by biolayer interferometry. Intracellular Ca2+ mobilization of platelets was measured by FLIPR Tetra System using Fluo-4 AM (Fluo-4 acetoxymethyl). Platelet aggregation, thrombus formation, and bleeding Assay were assessed. Results:An oligosaccharide HS-11, depolymerized from fucosylated glycosaminoglycan from sea cucumber Holothuria fuscopunctata blocks the interaction of thrombin with PAR1 and PAR4 complex by directly binding to thrombin exosite II, and completely inhibits platelet signal transduction, including intracellular Ca2+ mobilization and protein phosphorylation. Furthermore, HS-11 potently inhibits thrombin-PARs-mediated platelet aggregation and reduces thrombus formation in a model of ex vivo thrombosis. Conclusions:The study firstly report that the fucosylated glycosaminoglycan oligosaccharide has antiplatelet activity by binding to thrombin exosite II, and demonstrates that thrombin exosite II plays an important role in the simultaneous activation of PAR1 and PAR4, which may be a potential antithrombotic target for effective treatment of arterial thrombosis.
关键词	oligosaccharide platelet activation receptor protease-activated thrombin thrombosis ANTIPLATELET THERAPIES ALLOSTERIC LINKAGE TISSUE FACTOR PROTEASE VORAPAXAR MECHANISM REVEALS SITE
学科领域	Hematology ; Cardiovascular System & Cardiology
DOI	10.1161/ATVBAHA.122.318085
WOS记录号	WOS:000920978000013
引用统计
文献类型	期刊论文
条目标识符	http://ir.kib.ac.cn/handle/151853/74916
专题	中国科学院昆明植物研究所
推荐引用方式 GB/T 7714	Li,Sujuan,Wang,Weili,Lin,Lisha,et al. Oligosaccharide Blocks PAR1 (Proteinase-Activated Receptor 1)-PAR4-Mediated Platelet Activation by Binding to Thrombin Exosite II and Impairs Thrombosis[J]. ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY,2023,43(2):253-266.
APA	Li,Sujuan.,Wang,Weili.,Lin,Lisha.,Yang,Lian.,Cai,Ying.,...&Zhao,Jinhua.(2023).Oligosaccharide Blocks PAR1 (Proteinase-Activated Receptor 1)-PAR4-Mediated Platelet Activation by Binding to Thrombin Exosite II and Impairs Thrombosis.ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY,43(2),253-266.
MLA	Li,Sujuan,et al."Oligosaccharide Blocks PAR1 (Proteinase-Activated Receptor 1)-PAR4-Mediated Platelet Activation by Binding to Thrombin Exosite II and Impairs Thrombosis".ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY 43.2(2023):253-266.

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