VAMP8/endobrevin is overexpressed in hyperreactive human platelets: suggested role for platelet microRNA

Background: Variation in platelet reactivity contributes to disorders of hemostasis and thrombosis, but the molecular mechanisms are not well understood. Objectives: To discover associations between interindividual platelet variability and the responsible platelet genes, and to begin to define the m...

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Veröffentlicht in:Journal of thrombosis and haemostasis Jg. 8; H. 2; S. 369 - 378
Hauptverfasser: KONDKAR, A. A., BRAY, M. S., LEAL, S. M., NAGALLA, S., LIU, D. J., JIN, Y., DONG, J. F., REN, Q., WHITEHEART, S. W., SHAW, C., BRAY, P. F.
Format: Journal Article
Sprache:Englisch
Veröffentlicht: Oxford, UK Blackwell Publishing Ltd 01.02.2010
Schlagworte:
3' Untranslated Regions
Adult
Age Factors
Binding Sites
Blood Platelets - metabolism
Epinephrine
Female
Gene Expression Profiling - methods
Genotype
HCT116 Cells
Humans
Male
microRNA
MicroRNAs - blood
Oligonucleotide Array Sequence Analysis
Phenotype
Platelet Aggregation - genetics
platelet reactivity
polymorphism
Polymorphism, Single Nucleotide
R-SNARE Proteins - blood
R-SNARE Proteins - genetics
Reproducibility of Results
Reverse Transcriptase Polymerase Chain Reaction
RNA expression
RNA, Messenger - blood
Transfection
Up-Regulation
VAMP8
Young Adult
ISSN:1538-7933, 1538-7836, 1538-7836
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Zusammenfassung:Background: Variation in platelet reactivity contributes to disorders of hemostasis and thrombosis, but the molecular mechanisms are not well understood. Objectives: To discover associations between interindividual platelet variability and the responsible platelet genes, and to begin to define the molecular mechanisms altering platelet gene expression. Subjects/methods: Two hundred and eighty‐eight healthy subjects were phenotyped for platelet responsiveness. Platelet RNA from subjects demonstrating hyperreactivity (n = 18) and hyporeactivity (n = 11) was used to screen the human transcriptome. Results: Distinctly different mRNA profiles were observed between subjects with differing platelet reactivity. Increased levels of mRNA for VAMP8/endobrevin, a critical v‐SNARE involved in platelet granule secretion, were associated with platelet hyperreactivity (Q = 0.0275). Validation studies of microarray results showed 4.8‐fold higher mean VAMP8 mRNA levels in hyperreactive than hyporeactive platelets (P = 0.0023). VAMP8 protein levels varied 13‐fold among platelets from these normal subjects, and were 2.5‐fold higher in hyperreactive platelets (P = 0.05). Among our cohort of 288 subjects, a VAMP8 single‐nucleotide polymorphism (rs1010) was associated with platelet reactivity in an age‐dependent manner (P < 0.003). MicroRNA‐96 was predicted to bind to the 3′‐untranslated regionof VAMP8 mRNA and was detected in platelets. Overexpression of microRNA‐96 in VAMP8‐expressing cell lines caused a dose‐dependent decrease in VAMP8 protein and mRNA, suggesting a role in VAMP8 mRNA degradation. Conclusions: These findings support a role for VAMP8/endobrevin in the heterogeneity of platelet reactivity, and suggest a role for microRNA‐96 in the regulation of VAMP8 expression.
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ISSN:1538-7933
1538-7836
1538-7836
DOI:10.1111/j.1538-7836.2009.03700.x