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Background

Platelet ADP receptor P2Y(12) is well studied and recognized as a key player in platelet activation, hemostasis and thrombosis. However, the role of P2Y(12) in platelet apoptosis remains unknown.

Objectives

To evaluate the role of the 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."xsd:string
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http://purl.uniprot.org/citations/23140172http://purl.uniprot.org/core/author"Liu J."xsd:string
http://purl.uniprot.org/citations/23140172http://purl.uniprot.org/core/author"Zhang Y."xsd:string
http://purl.uniprot.org/citations/23140172http://purl.uniprot.org/core/author"Zhang S."xsd:string
http://purl.uniprot.org/citations/23140172http://purl.uniprot.org/core/author"Xu X."xsd:string
http://purl.uniprot.org/citations/23140172http://purl.uniprot.org/core/author"Ye J."xsd:string
http://purl.uniprot.org/citations/23140172http://purl.uniprot.org/core/author"Ding Z."xsd:string
http://purl.uniprot.org/citations/23140172http://purl.uniprot.org/core/author"Zhang S.H."xsd:string
http://purl.uniprot.org/citations/23140172http://purl.uniprot.org/core/author"Kunapuli S.P."xsd:string
http://purl.uniprot.org/citations/23140172http://purl.uniprot.org/core/date"2013"xsd:gYear
http://purl.uniprot.org/citations/23140172http://purl.uniprot.org/core/name"J Thromb Haemost"xsd:string
http://purl.uniprot.org/citations/23140172http://purl.uniprot.org/core/pages"149-160"xsd:string
http://purl.uniprot.org/citations/23140172http://purl.uniprot.org/core/title"P2Y12 protects platelets from apoptosis via PI3k-dependent Bak/Bax inactivation."xsd:string
http://purl.uniprot.org/citations/23140172http://purl.uniprot.org/core/volume"11"xsd:string
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