Transcriptome Analysis of Reticulated Platelets Reveals a Prothrombotic Profile
Transcriptome Analysis of Reticulated Platelets Reveals a Prothrombotic Profile
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DOI：
10.1055/s-0039-1695009
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发表时间：
2019-11-01
影响因子：
6.7
通讯作者：
Bernlochner, Isabell
中科院分区：
文献类型：
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作者：
Bongiovanni, Dario;Santamaria, Gianluca;Bernlochner, Isabell
网织血小板（RP）是较大的高反应性血小板，与成熟血小板（MP）相比，其含有显著更多的核糖核酸（RNA）。外周血中高水平的RP是心血管患者对双重抗血小板治疗反应不足和不良心血管事件的预测因子。然而，这些相关性的机制仍然是未知的，RPs的生物学尚未被研究。在这里，我们首次比较了从健康供体外周血中分离的RP和MP的转录组学谱。总RNA测序显示，与MP相比，RP中有1，744个差异表达基因（670个下调，1，074个上调）。特别地，胶原蛋白受体GP 6、血栓烷受体A2（TBXA 2R）、凝血酶受体PAR 4（F2 RL3）和三磷酸腺苷受体P2 RX 1、ORAI2和STIM 1（两者都参与钙信号传导）在RP中显著上调，而几种RNA调节因子如核糖核酸酶PARN，RISC组分TNRC6A，剪接因子LUC7L3在RP中表达下调。基因本体分析揭示了丰富的相关生物学类别的RP，包括血小板活化和凝血。基因集富集分析显示，在RP中，几种血小板活化途径（如凝血酶、血栓烷和糖蛋白IIb/IIIa信号传导）的表达过多。小RNA测序报告9个micro-RNA在RP中显著下调，靶点涉及血小板反应性。我们的数据显示，第一次丰富的几个血栓前转录的RP提供了第一个生物学解释其高反应性表型。
Reticulated platelets (RPs) are larger, hyperreactive platelets that contain significantly more ribonucleic acid (RNA) compared with mature platelets (MPs). High levels of RPs in peripheral blood are predictors of an insufficient response to dual antiplatelet therapy in cardiovascular patients and of adverse cardiovascular events. However, the mechanisms underlying these correlations remain widely unknown and the biology of RPs has not been investigated yet. Here, we compared for the first time the transcriptomic profiles of RPs and MPs isolated from peripheral blood of healthy donors. Total RNA sequencing revealed 1,744 differentially expressed genes (670 downregulated, 1,074 upregulated) in RPs compared with MPs. In particular, transcripts for the collagen receptor GP6 , thromboxane receptor A2 ( TBXA2R ), thrombin receptor PAR4 ( F2RL3 ), and adenosine triphosphate receptors P2RX1 , ORAI2 , and STIM1 (both involved in calcium signaling) were significantly upregulated in RPs, whereas several RNA regulators as the ribonuclease PARN , the RISC-component TNRC6A , and the splicing factor LUC7L3 were downregulated in RPs. Gene ontology analysis revealed an enrichment of relevant biological categories in RPs including platelet activation and blood coagulation. Gene Set Enrichment Analysis showed an overrepresentation of several platelet activation pathways like thrombin, thromboxane, and glycoprotein IIb/IIIa signaling in RPs. Small-RNA sequencing reported 9 micro-RNAs significantly downregulated in RPs with targets involved in platelet reactivity. Our data show for the first time an enrichment of several prothrombotic transcripts in RPs providing a first biological explanation for their hyperreactive phenotype.