These two authors contributed equally to this work.
P2Y12 protects platelets from apoptosis via PI3k-dependent Bak/Bax inactivation
Article first published online: 27 JAN 2013
© 2012 International Society on Thrombosis and Haemostasis
Journal of Thrombosis and Haemostasis
Volume 11, Issue 1, pages 149–160, January 2013
How to Cite
ZHANG, S., YE, J., ZHANG, Y., XU, X., LIU, J., ZHANG, S. H., KUNAPULI, S. P. and DING, Z. (2013), P2Y12 protects platelets from apoptosis via PI3k-dependent Bak/Bax inactivation. Journal of Thrombosis and Haemostasis, 11: 149–160. doi: 10.1111/jth.12063
- Issue published online: 27 JAN 2013
- Article first published online: 27 JAN 2013
- Accepted manuscript online: 12 NOV 2012 06:05AM EST
- Received 30 March 2012, accepted 1 November 2012
Summary. Background: Platelet ADP receptor P2Y12 is well studied and recognized as a key player in platelet activation, hemostasis and thrombosis. However, the role of P2Y12 in platelet apoptosis remains unknown. Objectives: To evaluate the role of the P2Y12 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 P2Y12 receptor antagonists or P2Y12-deficient mice. Results: P2Y12 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, P2Y12 activation inactivated Bak/Bax. This antiapoptotic effect could be abolished by P2Y12 antagonism or PI3K inhibition. We also observed the antiapoptotic effect of P2Y12 activation in platelets stored at 37 °C. P2Y12 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 P2Y12 receptor enhanced apoptosis along with increased Bak/Bax activation. Conclusions: This study demonstrates that P2Y12 activation protects platelets from apoptosis via PI3k-dependent Bak/Bax inactivation, which may be physiologically important to counter the proapoptotic challenge. Our findings that P2Y12 blockade exaggerates platelet apoptosis induced by ABT-263 (Navitoclax) also imply a novel drug interaction of ABT-263 and P2Y12 antagonists.