Molecular analysis of heterogeneity in human platelet aggregation response

精氨酸加压素(AVP)对血小板聚集的反应在个体间存在显著差异。在本研究中，高通量微阵列分析被用来探索导致异质性的分子。用血小板聚集分析仪MCM血细胞分析仪(PAM-12C型)对有反应和无反应的患者进行分类。日立Ace基因微阵列分析显示了特有的基因表达谱。也就是说，应答的血小板增加了钠通道、电压门控型、α，甘露糖-β-二醇利用缺陷1、真核翻译终止因子1、半胱氨酸和富含甘氨酸的蛋白2、和通用转录因子IIH多肽2 44 kDa的基因表达。在无应答者血小板中，低聚高尔基复合体成分6、Hermansky-Pudlak综合征3、PERM结构域含有1、单磷酸腺苷脱氨酶2(异构体L)nudex型基序1、和细胞生长调节因子1环指结构域1。质谱仪分析显示，在应答者中，蛋白水解酶丝氨酸4异构体B、和角蛋白1b、胰酶家族的蛋白水平升高，在无应答者中，TPMsk1、TPM3蛋白、、和YWHAZ蛋白的水平升高。AVP刺激的外周血CD34(+)干细胞(巨核祖细胞)中hsA let 7d、hsa let 7E、hsa miR198、、hsa miR99b、和hsa miR98水平也升高。AVP VLA受体基因242C/T多态性与其基因表达相关。从这些结果来看，许多因素可能是AVP引起的血小板聚集反应个体间异质性的原因。

There is a significant inter-individual divergence in the platelet aggregation response to arginine vasopressin (AVP). In the present study, high-throughput microarray analysis was conducted to explore molecules, which are responsible for the heterogeneity. Responders and non-responders were divided using platelet aggregation analyzer MCM hematracer 313 (Model PAM-12C). Hitachi Ace-Gene micro array analysis showed characteristic gene expression profiling. Namely, responder platelets had increased gene expressions of sodium channel, voltage-gated, type., alpha, mannose-P-dolichol utilization defect 1、eukaryotic translation termination factor 1、cysteine and glycine-rich protein 2、and general transcription factor IIH, polypeptide 2,44kDa. In non-responder platelets, genes including component of oligomeric golgi complex 6、Hermansky-Pudlak syndrome 3、PERM domain containing 1、adenosine monophosphate deaminase 2 (isoform L) nudix-type motif 1、and cell growth regulator with ring finger domain 1 were upregulated. Mass spectrometry analysis demonstrated increased platelet protein levels of protease serine 4 isoform B、and keratin 1b、trypsin family in responders and of TPMsk1、TPM3 protein、and YWHAZ protein in non-responders. There were also increased microRNA levels including hsa let 7d、hsa let 7e、hsa miR 198、hsa miR 99b、and hsa miR 98 in AVP stimulated peripheral CD34(+) stem cells (megakaryocyte progenitor cells). AVP Vla receptor gene polymorphism 242C/T showed an association with its gene expression. From these results, numbers of factors were likely to be responsible for the inter-individual heterogeneity in the platelet aggregation response to AVP.