| Autor: |
Mitrugno A; a Department of Biomedical Engineering, School of Medicine , Oregon Health & Science University , Portland , OR , USA.; b Cell, Developmental & Cancer Biology , School of Medicine, Oregon Health & Science University , Portland , OR , USA.; c Division of Hematology & Medical Oncology , School of Medicine, Oregon Health & Science University , Portland , OR , USA., Rigg RA; a Department of Biomedical Engineering, School of Medicine , Oregon Health & Science University , Portland , OR , USA., Laschober NB; a Department of Biomedical Engineering, School of Medicine , Oregon Health & Science University , Portland , OR , USA., Ngo ATP; a Department of Biomedical Engineering, School of Medicine , Oregon Health & Science University , Portland , OR , USA., Pang J; a Department of Biomedical Engineering, School of Medicine , Oregon Health & Science University , Portland , OR , USA., Williams CD; d School of Pharmacy, Oregon State University , Portland , OR , USA., Aslan JE; e School of Medicine, Knight Cardiovascular Institute, Oregon Health & Science University , Portland , OR , USA., McCarty OJT; a Department of Biomedical Engineering, School of Medicine , Oregon Health & Science University , Portland , OR , USA.; b Cell, Developmental & Cancer Biology , School of Medicine, Oregon Health & Science University , Portland , OR , USA.; c Division of Hematology & Medical Oncology , School of Medicine, Oregon Health & Science University , Portland , OR , USA. |
| Abstrakt: |
The release of ADP from platelet dense granules and its binding to platelet P2Y 12 receptors is key to amplifying the initial hemostatic response and propagating thrombus formation. P2Y 12 has thus emerged as a therapeutic target to safely and effectively prevent secondary thrombotic events in patients with acute coronary syndrome or a history of myocardial infarction. Pharmacological inhibition of P2Y 12 receptors represents a useful approach to better understand the signaling mediated by these receptors and to elucidate the role of these receptors in a multitude of platelet hemostatic and thrombotic responses. The present work examined and compared the effects of four different P2Y 12 inhibitors (MRS2395, ticagrelor, PSB 0739, and AR-C 66096) on platelet function in a series of in vitro studies of platelet dense granule secretion and trafficking, calcium generation, and protein phosphorylation. Our results show that in platelets activated with the PAR-1 agonist TRAP-6 (thrombin receptor-activating peptide), inhibition of P2Y 12 with the antagonist MRS2395, but not ticagrelor, PSB 0739 or AR-C 66096, potentiated human platelet dense granule trafficking to the plasma membrane and release into the extracellular space, cytosolic Ca 2+ influx, and phosphorylation of GSK3β-Ser9 through a PKC-dependent pathway. These results suggest that inhibition of P2Y 12 with MRS2395 may act in concert with PAR-1 signaling and result in the aberrant release of ADP by platelet dense granules, thus reducing or counteracting the anticipated anti-platelet efficacy of this inhibitor. |
