Racial differences in human platelet PAR4 reactivity reflect expression of PCTP and miR-376c

Abstract

Racial differences in the pathophysiology of atherothrombosis are poorly understood. We explored the function and transcriptome of platelets in healthy black (n = 70) and white (n = 84) subjects. PAR4 thrombin receptor induced platelet aggregation and calcium mobilization were significantly greater in black subjects. Numerous differentially expressed (DE) RNAs were associated with both race and PAR4 reactivity, including phosphatidylcholine transfer protein (PCTP), and platelets from blacks expressed higher levels of PC-TP protein. PC-TP inhibition or depletion blocked activation of platelets or megakaryocytic cell lines through PAR4 but not PAR1. MiR-376c levels were DE by race and PAR4 reactivity, and were inversely correlated with PCTP mRNA levels, PC-TP protein levels and PAR4 reactivity. MiR-376c regulated expression of PC-TP in human megakaryocytes. A disproportionately high number of miRNAs DE by race and PAR4 reactivity, including miR-376c, are encoded in the DLK1-DIO3 locus, and were lower in platelets from blacks. These results support PC-TP as a regulator of the racial difference in PAR4-mediated platelet activation, indicate a genomic contribution to platelet function that differs by race, and emphasize a need to consider race effects when developing anti-thrombotic drugs.

Nouvelle Cuisine: Platelets Served with Inflammation

“…These molecules in platelets may come from different sources, such as those inherited from megakaryocytes, those absorbed from the plasma, or those generated de novo. With regard to de novo synthesis of molecules in platelets, although platelets are anucleate, they express significant amounts of RNA, including mRNAs (e.g., premature and mature RNA), structural and catalytic RNAs (e.g., ribosomal and tRNA), regulatory RNAs (e.g., microRNA), and noncoding RNA (e.g., anti-sense RNA) (90)(91)(92)(93)(94)(95)(96)(97)(98)(99)(100)(101)(102)(103)(104)(105). More recently, it also was revealed that platelets contain all of the molecular machinery to translate mRNA into proteins, and they have the ability to transfer RNA to recipient cells where it can regulate cellular function (101-104).…”

The clinical significance of platelet microparticle-associated microRNAs

“…Two years later, Edelstein et al [29] narrowed the gap by showing that (i) miR-376c levels were inversely correlated with PCTP mRNA levels, PC-TP protein levels and PAR4 reactivity, and that (ii) miR376c regulated expression of PC-TP in human megakaryocytes [29].…”

Anti–miR-148a regulates platelet FcγRIIA signaling and decreases thrombosis in vivo in mice

“…13,35 Briefly, platelet-rich plasma aggregation assay via FcgRIIA was conducted on 154 human healthy donors as part of the PRAX-1 study.…”