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P2Y(12) protects platelets from apoptosis via PI3k-dependent bak/bax inactivation.
MedLine Citation:
PMID:  23140172     Owner:  NLM     Status:  Publisher    
Abstract/OtherAbstract:
Background: Platelet ADP receptor P2Y(12) is well studied and recognized as a key player in platelet activation, haemostasis and thrombosis. However, the role of P2Y(12) in platelet apoptosis remains unknown. Objectives: To evaluate the role of P2Y(12) receptor in platelet apoptosis. Methods: We used flow cytometry and western blotting to assess apoptotic events in platelets treated with ABT-737 or ABT-263, and stored at 37°C, combined with P2Y(12) receptor antagonists or P2Y(12) deficient mice Results: P2Y(12) activation attenuated apoptosis induced by ABT-737 in human and mouse platelets in vitro, evidenced by reduced phosphatidylserine (PS) exposure, diminished depolarization of mitochondrial inner transmembrane potential (ΔΨm), and decreased caspase-3 activation. Through increasing the phosphorylation level of Akt and Bad, and changing the interaction between different Bcl-2 family proteins, P2Y(12) activation inactivated Bak/Bax. This antiapoptotic effect could be abolished by P2Y(12) antagonism or PI3K inhibition. We also observed the antiapoptotic effect of P2Y(12) activation in platelets stored at 37°C. P2Y(12) activation improved the impaired activation responses of apoptotic platelets stressed by ABT-737. In platelets from mice dosed with ABT-263 in vivo, clopidogrel or deficiency of P2Y(12) receptor enhanced apoptosis along with increased Bak/Bax activation. Conclusions: This study demonstrates that P2Y(12) activation protects platelets from apoptosis via PI3k-dependent Bak/Bax inactivation, which may be physiologically important to counter the proapoptotic challenge. Our findings that P2Y(12) blockade exaggerates platelet apoptosis induced by ABT-263 (Navitoclax) also imply a novel drug interaction of ABT-263 and P2Y(12) antagonists. © 2012 International Society on Thrombosis and Haemostasis.
Authors:
S Zhang; J Ye; Y Zhang; X Xu; J Liu; S H Zhang; S P Kunapuli; Z Ding
Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2012-11-12
Journal Detail:
Title:  Journal of thrombosis and haemostasis : JTH     Volume:  -     ISSN:  1538-7836     ISO Abbreviation:  J. Thromb. Haemost.     Publication Date:  2012 Nov 
Date Detail:
Created Date:  2012-11-12     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  101170508     Medline TA:  J Thromb Haemost     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
Copyright Information:
© 2012 International Society on Thrombosis and Haemostasis.
Affiliation:
Key Laboratory of Molecular Medicine, Ministry of Education, and Department of Biochemistry and Molecular Biology, Fudan University Shanghai Medical College, Shanghai, China Department of Clinical Laboratory, Fudan University Shanghai Cancer Center, Shanghai, China Department of Biochemistry and Molecular & Cell Biology, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Institute of Medical Science, Shanghai Jiao Tong University School of Medicine, Shanghai, China Department of Physiology and the Sol Sherry Thrombosis Research Center, Temple University School of Medicine, Philadelphia, Pennsylvania, USA.
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