期刊
JOURNAL OF THROMBOSIS AND HAEMOSTASIS
卷 6, 期 6, 页码 995-1002出版社
WILEY-BLACKWELL
DOI: 10.1111/j.1538-7836.2008.02979.x
关键词
activated protein C; apolipoprotein E receptor 2; glycoprotein Ib; platelet activation
资金
- NHLBI NIH HHS [HL31950, HL52246, P01 HL031950, HL73813] Funding Source: Medline
- NATIONAL HEART, LUNG, AND BLOOD INSTITUTE [R01HL073813, P01HL031950, R37HL052246, R01HL052246] Funding Source: NIH RePORTER
Background: Activated protein C (APC) regulates thrombin generation and inhibits apoptosis. Endothelial protein C receptor (EPCR)-bound protein C is activated by thrombomodulin-bound thrombin. APC inactivates coagulation factors (F)Va/VIIIa and generates cytoprotective signaling downstream of protease-activated receptor-1 (PAR-1). Binding of APC to EPCR both modifies and induces PAR-1 signaling, but it is unknown if protein C interacts with cells in an alternative manner. Aim: To determine whether platelets possess receptors for protein C that can generate intracellular signals. Results: Immobilized protein C or APC supported platelet adhesion, lamellipodia formation and elevation of intracellular Ca2+. Adhesion of platelets to protein C or APC was inhibited by soluble recombinant apolipoprotein E receptor 2' (ApoER2') and by receptor-associated protein (RAP), an inhibitor of the low-density lipoprotein receptor family. Under shear, surface-bound protein C supported platelet adhesion and aggregation in a glycoprotein (GP)Ib alpha-dependent manner, and adhesion of platelets to immobilized protein C was abrogated by the addition of soluble forms of ApoER2' or RAP. APC bound to purified recombinant ApoER2' or GPIb alpha. Conclusions: Our data demonstrate that activation of platelets with rapid intracellular signaling caused by binding to immobilized protein C or APC occurs via mechanisms that require ApoER2 and GPIb alpha and that APC directly binds to purified ectodomains of the receptors ApoER2 and GPIb alpha. These findings imply that protein C and APC may directly promote cell signaling in other cells by binding to ApoER2 and/or GPIb alpha.
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