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

In exploring the possibility that racial differences in platelet function might exist, Paul Bray and his colleagues report that platelets from blacks have a greater propensity to aggregate than those from whites in response to activation of the PAR4 thrombin receptor. Mechanistically, this differenc...

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Vydané v:Nature medicine Ročník 19; číslo 12; s. 1609 - 1616
Hlavní autori: Edelstein, Leonard C, Simon, Lukas M, Montoya, Raúl Teruel, Holinstat, Michael, Chen, Edward S, Bergeron, Angela, Kong, Xianguo, Nagalla, Srikanth, Mohandas, Narla, Cohen, David E, Dong, Jing-fei, Shaw, Chad, Bray, Paul F
Médium: Journal Article
Jazyk:English
Vydavateľské údaje: New York Nature Publishing Group US 01.12.2013
Nature Publishing Group
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Atherosclerosis
Biomedicine
Blood platelets
Blood Platelets - metabolism
Calcium
Cancer Research
Carrier proteins
Cell receptors
Cells, Cultured
Continental Population Groups - genetics
Demographic aspects
Embolism, Cholesterol - ethnology
Embolism, Cholesterol - genetics
Embolism, Cholesterol - metabolism
Gene expression
Genetic aspects
HCT116 Cells
Hep G2 Cells
Humans
Identification and classification
Infectious Diseases
Metabolic Diseases
MicroRNAs - genetics
Molecular Medicine
Neurosciences
Phospholipid Transfer Proteins - genetics
Phospholipid Transfer Proteins - metabolism
Platelet Aggregation - genetics
Racial differences
Receptors, Thrombin - metabolism
Studies
Thrombolytic drugs
Thrombosis - ethnology
Thrombosis - genetics
Thrombosis - metabolism
United States > US
ISSN:1078-8956, 1546-170X, 1546-170X
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Shrnutí:In exploring the possibility that racial differences in platelet function might exist, Paul Bray and his colleagues report that platelets from blacks have a greater propensity to aggregate than those from whites in response to activation of the PAR4 thrombin receptor. Mechanistically, this difference in platelet function seems to reflect differences in the expression of the microRNA miR-376c and its target, the enzyme phosphatidylcholine transfer protein. 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. Platelet aggregation and calcium mobilization induced by the PAR4 thrombin receptor were significantly greater in black subjects. Numerous differentially expressed RNAs were associated with both race and PAR4 reactivity, including PCTP (encoding phosphatidylcholine transfer protein), and platelets from black subjects expressed higher levels of PC-TP protein. PC-TP inhibition or depletion blocked PAR4- but not PAR1-mediated activation of platelets and megakaryocytic cell lines. miR-376c levels were differentially expressed by race and PAR4 reactivity and were inversely correlated with PCTP mRNA levels, PC-TP protein levels and PAR4 reactivity. miR-376c regulated the expression of PC-TP in human megakaryocytes. A disproportionately high number of microRNAs that were differentially expressed by race and PAR4 reactivity, including miR-376c , are encoded in the DLK1-DIO3 locus and were expressed at lower levels in platelets from black subjects. These results suggest that PC-TP contributes to 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 the effects of race when developing anti-thrombotic drugs.
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ISSN:1078-8956
1546-170X
1546-170X
DOI:10.1038/nm.3385