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

Leonard C. Edelstein, Lukas M. Simon, Raúl Teruel Montoya, Michael Holinstat, Edward S. Chen, Angela Bergeron, Xianguo Kong, Srikanth Nagalla, Narla Mohandas, David E. Cohen, Jing Fei Dong, Chad Shaw, Paul F. Bray

Research output: Contribution to journalArticle

95 Citations (Scopus)

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. 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.

Original languageEnglish (US)
Pages (from-to)1609-1616
Number of pages8
JournalNature Medicine
Volume19
Issue number12
DOIs
StatePublished - Dec 1 2013

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Phospholipid Transfer Proteins
Platelets
Blood Platelets
Platelet Activation
Thrombin Receptors
Megakaryocytes
Chemical activation
MicroRNAs
Platelet Aggregation
Transcriptome
Proteins
RNA
Calcium
Cell Line
Messenger RNA
Agglomeration
Cells
Pharmaceutical Preparations

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Edelstein, L. C., Simon, L. M., Montoya, R. T., Holinstat, M., Chen, E. S., Bergeron, A., ... Bray, P. F. (2013). Racial differences in human platelet PAR4 reactivity reflect expression of PCTP and miR-376c. Nature Medicine, 19(12), 1609-1616. https://doi.org/10.1038/nm.3385

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

In: Nature Medicine, Vol. 19, No. 12, 01.12.2013, p. 1609-1616.

Research output: Contribution to journalArticle

Edelstein, LC, Simon, LM, Montoya, RT, Holinstat, M, Chen, ES, Bergeron, A, Kong, X, Nagalla, S, Mohandas, N, Cohen, DE, Dong, JF, Shaw, C & Bray, PF 2013, 'Racial differences in human platelet PAR4 reactivity reflect expression of PCTP and miR-376c', Nature Medicine, vol. 19, no. 12, pp. 1609-1616. https://doi.org/10.1038/nm.3385
Edelstein LC, Simon LM, Montoya RT, Holinstat M, Chen ES, Bergeron A et al. Racial differences in human platelet PAR4 reactivity reflect expression of PCTP and miR-376c. Nature Medicine. 2013 Dec 1;19(12):1609-1616. https://doi.org/10.1038/nm.3385
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. / Racial differences in human platelet PAR4 reactivity reflect expression of PCTP and miR-376c. In: Nature Medicine. 2013 ; Vol. 19, No. 12. pp. 1609-1616.
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