Receptor-interacting protein kinase 3 promotes platelet activation and thrombosis.

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.

• Authors: 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
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 114 Issue 11 Pg. 2964-2969 (03 14 2017) ISSN: 1091-6490 [Electronic] United States
• PMID: 28242694 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Phosphatidylserines
• Thromboxane A2
• Adenosine Diphosphate
• Proto-Oncogene Proteins c-akt
• RIPK3 protein, human
• Receptor-Interacting Protein Serine-Threonine Kinases
• Thrombin

Topics

• Adenosine Diphosphate (metabolism)
• Animals
• Blood Platelets (metabolism)
• Disease Models, Animal
• Gene Expression
• Hemostasis (genetics)
• Humans
• Mice
• Mice, Knockout
• Phosphatidylserines (metabolism)
• Phosphorylation
• Platelet Activation (genetics)
• Platelet Aggregation (genetics)
• Proto-Oncogene Proteins c-akt (metabolism)
• Receptor-Interacting Protein Serine-Threonine Kinases (genetics, metabolism)
• Signal Transduction
• Thrombin (metabolism)
• Thrombosis (genetics, metabolism)
• Thromboxane A2 (metabolism)