title: 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 inRIP3-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 A2analog, U46619. Phosphorylation of Akt induced by U46619 or thrombin was diminished in RIP3-/-platelets. Moreover, RIP3 interacted with Gα13Platelet 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.affiliation: Jiangsu Institute of Hematology, The First Affiliated Hospital, Collaborative Innovation Center of Hematology, Soochow University, Key Laboratory of Thrombosis and Hemostasis, Ministry of Health, Suzhou 215006, China.
authors.forename: Yiwen
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Jiangsu Institute of Hematology, The First Affiliated Hospital, Collaborative Innovation Center of Hematology, Soochow University, Key Laboratory of Thrombosis and Hemostasis, Ministry of Health, Suzhou 215006, China.
authors.forename: Jian
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Jiangsu Institute of Hematology, The First Affiliated Hospital, Collaborative Innovation Center of Hematology, Soochow University, Key Laboratory of Thrombosis and Hemostasis, Ministry of Health, Suzhou 215006, China.
authors.forename: Rong
authors.initials: R
authors.lastname: Yan
authors.affiliation: Jiangsu Institute of Hematology, The First Affiliated Hospital, Collaborative Innovation Center of Hematology, Soochow University, Key Laboratory of Thrombosis and Hemostasis, Ministry of Health, Suzhou 215006, China.
authors.forename: Jingluan
authors.initials: J
authors.lastname: Tian
authors.affiliation: Jiangsu Institute of Hematology, The First Affiliated Hospital, Collaborative Innovation Center of Hematology, Soochow University, Key Laboratory of Thrombosis and Hemostasis, Ministry of Health, Suzhou 215006, China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Jiangsu Institute of Hematology, The First Affiliated Hospital, Collaborative Innovation Center of Hematology, Soochow University, Key Laboratory of Thrombosis and Hemostasis, Ministry of Health, Suzhou 215006, China.
authors.forename: Jie
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Jiangsu Institute of Hematology, The First Affiliated Hospital, Collaborative Innovation Center of Hematology, Soochow University, Key Laboratory of Thrombosis and Hemostasis, Ministry of Health, Suzhou 215006, China.
authors.forename: Mengxing
authors.initials: M
authors.lastname: Chen
authors.affiliation: Jiangsu Institute of Hematology, The First Affiliated Hospital, Collaborative Innovation Center of Hematology, Soochow University, Key Laboratory of Thrombosis and Hemostasis, Ministry of Health, Suzhou 215006, China.
authors.forename: Qingya
authors.initials: Q
authors.lastname: Cui
authors.affiliation: Jiangsu Institute of Hematology, The First Affiliated Hospital, Collaborative Innovation Center of Hematology, Soochow University, Key Laboratory of Thrombosis and Hemostasis, Ministry of Health, Suzhou 215006, China.
authors.forename: Lili
authors.initials: L
authors.lastname: Zhao
authors.affiliation: Jiangsu Institute of Hematology, The First Affiliated Hospital, Collaborative Innovation Center of Hematology, Soochow University, Key Laboratory of Thrombosis and Hemostasis, Ministry of Health, Suzhou 215006, China.
authors.forename: Renping
authors.initials: R
authors.lastname: Hu
authors.affiliation: Jiangsu Institute of Hematology, The First Affiliated Hospital, Collaborative Innovation Center of Hematology, Soochow University, Key Laboratory of Thrombosis and Hemostasis, Ministry of Health, Suzhou 215006, China.
authors.forename: Miao
authors.initials: M
authors.lastname: Jiang
authors.affiliation: Department of Internal Medicine, University of Kentucky, Lexington, KY 40506.
authors.forename: Zhenyu
authors.initials: Z
authors.lastname: Li
authors.affiliation: Jiangsu Institute of Hematology, The First Affiliated Hospital, Collaborative Innovation Center of Hematology, Soochow University, Key Laboratory of Thrombosis and Hemostasis, Ministry of Health, Suzhou 215006, China.
authors.forename: Changgeng
authors.initials: C
authors.lastname: Ruan
authors.affiliation: The Cyrus Tang Hematology Center and Collaborative Innovation Center of Hematology, Soochow University, Key Laboratory of Thrombosis and Hemostasis, Ministry of Health, Suzhou 215006, China.
authors.forename: Sudan
authors.initials: S
authors.lastname: He
authors.affiliation: Jiangsu Institute of Hematology, The First Affiliated Hospital, Collaborative Innovation Center of Hematology, Soochow University, Key Laboratory of Thrombosis and Hemostasis, Ministry of Health, Suzhou 215006, China; kdai@suda.edu.cn.
authors.forename: Kesheng
authors.initials: K
authors.lastname: Dai
mesh_terms: D000244:Adenosine Diphosphate / Q000378:metabolism; D000818:Animals; D001792:Blood Platelets / Q000378:metabolism; D004195:Disease Models, Animal; D015870:Gene Expression; D006487:Hemostasis / Q000235:genetics; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D010718:Phosphatidylserines / Q000378:metabolism; D010766:Phosphorylation; D015539:Platelet Activation / Q000235:genetics*; D010974:Platelet Aggregation / Q000235:genetics; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D053422:Receptor-Interacting Protein Serine-Threonine Kinases / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D013917:Thrombin / Q000378:metabolism; D013927:Thrombosis / Q000235:genetics* / Q000378:metabolism*; D013928:Thromboxane A2 / Q000378:metabolism
chemical_list: D010718:Phosphatidylserines; D013928:Thromboxane A2; D000244:Adenosine Diphosphate; D051057:Proto-Oncogene Proteins c-akt; C119705:RIPK3 protein, human; D053422:Receptor-Interacting Protein Serine-Threonine Kinases; D013917:Thrombin
keywords: platelets; receptor-interacting protein kinase 3; thrombin; thrombosis; thromboxane A2