文章基本信息

标题：Receptor-interacting protein kinase 3 promotes platelet activation and thrombosis
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作者：Yiwen Zhang ; Jian Zhang ; Rong Yan 等
期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2017
卷号：114
期号：11
页码：2964-2969
DOI：10.1073/pnas.1610963114
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：Previous studies have shown that receptor-interacting protein kinase 3 (RIP3) is involved in many important biological processes, including necroptosis, apoptosis, and inflammation. Here we show that RIP3 plays a critical role in regulating platelet functions and in vivo thrombosis and hemostasis. Tail bleeding times were significantly longer in RIP3 -knockout (RIP3^−/−) mice compared with their wild-type (WT) littermates. In an in vivo model of arteriole thrombosis, mice lacking RIP3 exhibited prolonged occlusion times. WT mice repopulated with RIP3^−/− bone marrow-derived cells had longer occlusion times than RIP3^−/− mice repopulated with WT bone marrow-derived cells, suggesting a role for RIP3-deficient platelets in arterial thrombosis. Consistent with these findings, we observed that RIP3 was expressed in both human and mice platelets. Deletion of RIP3 in mouse platelets caused a marked defect in aggregation and attenuated dense granule secretion in response to low doses of thrombin or a thromboxane A₂ analog, U46619. Phosphorylation of Akt induced by U46619 or thrombin was diminished in RIP3^−/− platelets. Moreover, RIP3 interacted with Gα₁₃. Platelet spreading on fibrinogen and clot retraction were impaired in the absence of RIP3. RIP3 inhibitor dose-dependently inhibited platelet aggregation in vitro and prevented arterial thrombus formation in vivo. These data demonstrate a role for RIP3 in promoting in vivo thrombosis and hemostasis by amplifying platelet activation. RIP3 may represent a novel promising therapeutic target for thrombotic diseases.
关键词：platelets ; receptor-interacting protein kinase 3 ; thrombin ; thromboxane A2 ; thrombosis