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2015年11月,血栓与止血研究部武艺博士课题组在J Clin Invest上发表文章

发布日期:2015/11/06

2015年11月,武艺博士课题组在J Clin Invest杂志上在线发表题为“The C-terminal CGHC motif of protein disulfide isomerase supports thrombosis”的文章。

 

J Clin Invest. 2015. doi:10.1172/JCI80319.

 

题目:

The C-terminal CGHC motif of protein disulfide isomerase supports thrombosis

 

作者:

Junsong Zhou1, Yi Wu1,2, Lu Wang2, Lubica Rauova3, Vincent M. Hayes3, Mortimer Poncz3, and David W. Essex2

 

单位:

 1 Cyrus Tang Hematology Center, Jiangsu Institute of Hematology, Collaborative Innovation Center of Hematology, Soochow University, Suzhou, China. 2 Sol Sherry Thrombosis Research Center, Division of Hematology, Department of Medicine, Temple University School of Medicine, Philadelphia, Pennsylvania, USA. 3 Division of Hematology, Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.

 

摘要:

Protein disulfide isomerase (PDI) has two distinct CGHC redox-active sites; however, the contribution of these sites during different physiologic reactions, including thrombosis, is unknown. Here, we evaluated the role of PDI and redox-active sitesof PDI in thrombosis by generating mice with blood cells and vessel wall cells lacking PDI (Mx1-Cre Pdifl/fl mice) and transgenic mice harboring PDI that lacks a functional C-terminal CGHC motif [PDI(ss-oo) mice]. Both mouse models showed decreased fibrin deposition and platelet accumulation in laser-induced cremaster arteriole injury, and PDI(ss-oo) mice had attenuated platelet accumulation in FeCl3-induced mesenteric arterial injury. These defects were rescued by infusion of recombinant PDI containing only a functional C-terminal CGHC motif [PDI(oo-ss)]. PDI infusion restored fibrin formation, but not platelet accumulation, in eptifibatide-treated wild-type mice, suggesting a direct role of PDI in coagulation. In vitro aggregation of platelets from PDI(ss-oo) mice and PDI-null platelets was reduced; however, this defect was rescued by recombinant PDI(oo- ss). In human platelets, recombinant PDI(ss-oo) inhibited aggregation, while recombinant PDI(oo-ss) potentiated aggregation. Platelet secretion assays demonstrated that the C-terminal CGHC motif of PDI is important for P-selectin expression and ATP secretion through a non-αIIbβ3 substrate. In summary, our results indicate that the C-terminal CGHC motif of PDI is important for platelet function and coagulation.

(This article is highlighted by J Clin Investin itsScientific Show Stopper: “Teasing apart active site contributions”)

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