title: Mechanism of race-dependent platelet activation through the protease-activated receptor-4 and Gq signaling axis.
abstract: OBJECTIVE
  Black individuals are at an increased risk of myocardial infarction and stroke, 2 vascular diseases with strong thrombotic components. Platelet activation is a key step in platelet clot formation leading to myocardial infarction and stroke, and recent work supports a racial difference in platelet aggregation through the thrombin protease-activated receptors (PARs). The underlying mechanism for this racial difference, however, has not been established. Determining where in the signaling cascade these racial differences emerge will aid in understanding why individuals of differing racial ancestry may possess an inherent difference in their responsiveness to antiplatelet therapies.
  
  
  RESULTS
  Washed human platelets from black volunteers were hyperaggregable in response to PAR4-mediated platelet stimulation compared with whites. Interestingly, the racial difference in PAR4-mediated platelet aggregation persisted in platelets treated ex vivo with aspirin and 2MeSAMP (2-methylthioadenosine 5'-monophosphate triethylammonium salt hydrate), suggesting that the racial difference is independent of secondary feedback. Furthermore, stimulation of platelets from black donors with PAR4-activating peptide showed a potentiated level of activation through the Gq pathway compared with platelets from white donors. Differences in signaling included increased Ca(2+) mobilization, Rap1 (Ras-related protein 1) activation, and integrin αIIbβ3 activation with no observed difference in platelet protein expression between the groups tested.
  
  
  CONCLUSIONS
  Our study is the first to demonstrate that the Gq pathway is differentially regulated by race after PAR4 stimulation in human platelets. Furthermore, the racial difference in PAR4-mediated platelet aggregation persisted in the presence of cyclooxygenase and P2Y12 receptor dual inhibition, suggesting that current antiplatelet therapy may provide less protection to blacks than whites.
authors.affiliation: From the Department of Medicine, Cardeza Foundation for Hematologic Research, Thomas Jefferson University, Philadelphia, PA.
authors.forename: Benjamin E
authors.initials: BE
authors.lastname: Tourdot
authors.affiliation: From the Department of Medicine, Cardeza Foundation for Hematologic Research, Thomas Jefferson University, Philadelphia, PA.
authors.forename: Stanley
authors.initials: S
authors.lastname: Conaway
authors.affiliation: From the Department of Medicine, Cardeza Foundation for Hematologic Research, Thomas Jefferson University, Philadelphia, PA.
authors.forename: Katrin
authors.initials: K
authors.lastname: Niisuke
authors.affiliation: From the Department of Medicine, Cardeza Foundation for Hematologic Research, Thomas Jefferson University, Philadelphia, PA.
authors.forename: Leonard C
authors.initials: LC
authors.lastname: Edelstein
authors.affiliation: From the Department of Medicine, Cardeza Foundation for Hematologic Research, Thomas Jefferson University, Philadelphia, PA.
authors.forename: Paul F
authors.initials: PF
authors.lastname: Bray
authors.affiliation: From the Department of Medicine, Cardeza Foundation for Hematologic Research, Thomas Jefferson University, Philadelphia, PA. michael.holinstat@jefferson.edu.
authors.forename: Michael
authors.initials: M
authors.lastname: Holinstat
mesh_terms: D000328:Adult; D044383:Black People; D020013:Calcium Signaling; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D005260:Female; D043802:GTP-Binding Protein alpha Subunits, Gq-G11 / Q000097:blood*; D006801:Humans; D008297:Male; D015539:Platelet Activation / Q000187:drug effects / Q000502:physiology*; D010974:Platelet Aggregation / Q000502:physiology; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000378:metabolism; D011451:Prostaglandin-Endoperoxide Synthases / Q000097:blood; D011493:Protein Kinase C / Q000097:blood; D058921:Purinergic P2Y Receptor Antagonists / Q000494:pharmacology; D058925:Receptors, Purinergic P2Y12 / Q000097:blood; D018179:Receptors, Thrombin / Q000097:blood*; D000089804:Shelterin Complex; D015398:Signal Transduction; D034501:Telomere-Binding Proteins / Q000097:blood; D044465:White People
chemical_list: D016861:Cyclooxygenase Inhibitors; C548576:P2RY12 protein, human; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; D058921:Purinergic P2Y Receptor Antagonists; D058925:Receptors, Purinergic P2Y12; D018179:Receptors, Thrombin; D000089804:Shelterin Complex; C440809:TERF2IP protein, human; D034501:Telomere-Binding Proteins; D011451:Prostaglandin-Endoperoxide Synthases; D011493:Protein Kinase C; D043802:GTP-Binding Protein alpha Subunits, Gq-G11; C112908:protease-activated receptor 4
keywords: blood platelet; continental population groups; protease-activated receptor 4; thrombin; thrombosis