VAMP8/endobrevin is overexpressed in hyperreactive human platelets: suggested role for platelet microRNA.
VAMP8/endobrevin is overexpressed in hyperreactive human platelets: suggested role for platelet microRNA.
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DOI：
10.1111/j.1538-7836.2009.03700.x
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发表时间：
2010-02
期刊：
影响因子：
--
通讯作者：
Bray PF
中科院分区：
文献类型：
--
作者：
Kondkar AA;Bray MS;Leal SM;Nagalla S;Liu DJ;Jin Y;Dong JF;Ren Q;Whiteheart SW;Shaw C;Bray PF
血小板反应性的变化会导致止血障碍和血栓形成，但其分子机制尚不清楚。发现个体间血小板变异性与负责的血小板基因之间的关联，并开始定义改变血小板基因表达的分子机制。对 288 名健康受试者进行了血小板反应性表型分析。来自表现出高反应性 (n = 18) 和低反应性 (n = 11) 的受试者的血小板 RNA 用于筛选人类转录组。在具有不同血小板反应性的受试者之间观察到明显不同的 mRNA 谱。 VAMP8/endobrevin（参与血小板颗粒分泌的关键 v-SNARE）mRNA 水平升高与血小板高反应性相关（Q = 0.0275）。微阵列结果的验证研究显示，高反应性血小板中的平均 VAMP8 mRNA 水平比低反应性血小板高 4.8 倍 (P = 0.0023)。这些正常受试者的血小板中，VAMP8 蛋白水平相差 13 倍，而高反应性血小板中的 VAMP8 蛋白水平则高出 2.5 倍 (P = 0.05)。 在我们的 288 名受试者队列中，VAMP8 单核苷酸多态性 (rs1010) 以年龄依赖性方式与血小板反应性相关 (P < 0.003)。 MicroRNA-96 预计会与 VAMP8 mRNA 的 3' 非翻译区结合，并在血小板中检测到。在表达 VAMP8 的细胞系中，microRNA-96 的过度表达导致 VAMP8 蛋白和 mRNA 呈剂量依赖性减少，表明其在 VAMP8 mRNA 降解中发挥作用。这些发现支持 VAMP8/endobrevin 在血小板反应性异质性中的作用，并表明 microRNA-96 在 VAMP8 表达调节中的作用。
Variation in platelet reactivity contributes to disorders of hemostasis and thrombosis, but the molecular mechanisms are not well understood. To discover associations between interindividual platelet variability and the responsible platelet genes, and to begin to define the molecular mechanisms altering platelet gene expression. 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. 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 region of 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. 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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