Receptor-interacting protein kinase 3 promotes platelet activation and thrombosis

Yiwen Zhang, Jian Zhang, Rong Yan, Jingluan Tian, Yang Zhang, Jie Zhang, Mengxing Chen, Qingya Cui, Lili Zhao, Renping Hu, Miao Jiang, Zhenyu Li, Changgeng Ruan, Sudan He, Kesheng Dai

Research output: Contribution to journalArticlepeer-review

34 Scopus citations

Abstract

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.

Original languageEnglish
Pages (from-to)2964-2969
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume114
Issue number11
DOIs
StatePublished - Mar 14 2017

Bibliographical note

Funding Information:
National Natural Science Foundation of China (81130008)

Keywords

  • Platelets
  • Receptor-Interacting Protein Kinase 3
  • Thrombin
  • Thrombosis
  • Thromboxane A2

ASJC Scopus subject areas

  • General

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