PDK1 regulates platelet activation and arterial thrombosis

被引：72

作者：

Chen, Xue ^{[1
]}

Zhang, Yue ^{[2
]}

Wang, Yanhua ^{[1
]}

Li, Ding ^{[1
]}

Zhang, Lin ^{[1
]}

Wang, Kemin ^{[1
]}

Luo, Xinping ^{[3
]}

Yang, Zhongzhou ^{[4
]}

Wu, Yi ^{[5
]}

Liu, Junling ^{[1
]}

机构：

[1] Shanghai Jiao Tong Univ, Sch Med, Ruijin Hosp, Dept Biochem & Mol Cell Biol,Shanghai Key Lab Tum, Shanghai 200025, Peoples R China

[2] Shanghai Jiao Tong Univ, Sch Med, Ruijin Hosp, Sino French Res Ctr Life Sci & Genom, Shanghai 200025, Peoples R China

[3] Fudan Univ, Huashan Hosp, Dept Cardiol, Shanghai 200433, Peoples R China

[4] Nanjing Univ, Minist Educ, Key Lab Model Anim Dis Study, Model Anim Res Ctr, Nanjing 210008, Jiangsu, Peoples R China

[5] Soochow Univ, Jiangsu Inst Hematol, Cyrus Tang Hematol Ctr, Affiliated Hosp 1, Suzhou, Peoples R China

来源：

BLOOD | 2013年 / 121卷 / 18期

基金：

中国国家自然科学基金;

关键词：

PROTEIN-KINASE-B; GLYCOGEN-SYNTHASE KINASE-3; SIGNALING PATHWAY; TYROSINE KINASE; DISTINCT ROLES; IN-VIVO; PHOSPHORYLATION; AKT; MICE; BINDING;

D O I：

10.1182/blood-2012-10-461897

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

The effects of phosphoinositide-dependent protein kinase 1 (PDK1), a master kinase in the phosphoinositide 3-kinase/Akt pathway, on platelet activation are unknown. Accordingly, platelet-specific PDK1-deficient mice were characterized to elucidate the platelet-related function(s) of PDK1. We found that PDK1 deficiency caused mild thrombocytopenia. The aggregation of PDK1(-/-) platelets was diminished in response to low levels of thrombin, U46619, and adenosine 5'-diphosphate. Further results demonstrated that PDK1 regulates thrombin-induced platelet activation by affecting alpha IIb beta 3-mediated outside-in signaling. This result provided an explanation for the diminished spreading of PDK1(-/-) platelets on immobilized fibrinogen (Fg) and the decreased rate of clot retraction in platelet-rich plasma (PRP) containing PDK1(-/-) platelets. PDK1 deficiency diminished agonist-induced Akt Ser473 phosphorylation and thoroughly abolished Akt Thr308 and Gsk3 beta Ser9 phosphorylation in response to agonist treatment and platelet spreading, respectively. A Gsk3b inhibitor fully restored the aggregation of PDK1(-/-) platelets in response to low levels of thrombin, normal spreading of PDK1(-/-) platelets on Fg, and normal clot retraction in PRP containing PDK1(-/-) platelets. Those results indicated that Gsk3b is one of the major downstream effectors of PDK1 in thrombin-induced platelet activation and alpha IIb beta 3-mediated outside-in signaling. In addition, in vivo data demonstrated that PDK1 is an important regulator in arterial thrombosis formation.

引用

页码：3718 / 3726

页数：9

共 48 条

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