TY - JOUR
T1 - Receptor-interacting protein kinase 3 promotes platelet activation and thrombosis
AU - Zhang, Yiwen
AU - Zhang, Jian
AU - Yan, Rong
AU - Tian, Jingluan
AU - Zhang, Yang
AU - Zhang, Jie
AU - Chen, Mengxing
AU - Cui, Qingya
AU - Zhao, Lili
AU - Hu, Renping
AU - Jiang, Miao
AU - Li, Zhenyu
AU - Ruan, Changgeng
AU - He, Sudan
AU - Dai, Kesheng
N1 - Funding Information:
National Natural Science Foundation of China (81130008)
PY - 2017/3/14
Y1 - 2017/3/14
N2 - 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.
AB - 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.
KW - Platelets
KW - Receptor-Interacting Protein Kinase 3
KW - Thrombin
KW - Thrombosis
KW - Thromboxane A2
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U2 - 10.1073/pnas.1610963114
DO - 10.1073/pnas.1610963114
M3 - Article
C2 - 28242694
AN - SCOPUS:85015447568
SN - 0027-8424
VL - 114
SP - 2964
EP - 2969
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 11
ER -