The role of miRNAs in regulation of platelet activity and related diseases - a bioinformatic analysis

MicroRNAs (miRNAs) are small, non-coding RNAs, able to regulate cellular functions by induction of mRNA degradation and post-transcriptional repression of gene expression. Platelets are the major source of circulating miRNAs, with significant regulatory potential on cardiovascular pathophysiology and other diseases. MiRNAs have been shown to modify the expression of platelet proteins, which influence the platelets reactivity. Circulating miRNAs can be determined from plasma, serum, or whole blood, and they can be used as diagnostic and prognostic biomarkers as well as therapeutic targets including cardiovascular diseases (CVDs). Herein, we present original results from bioinformatic analyses, which identified top 22 platelet-related miRNAs including hsa-miR-320a, hsa-miR-16-5p, hsa-miR-106a-5p, hsa-miR-320b, hsa-miR-15a-5p, hsa-miR-15b-5p, hsa-miR-195-5p, hsa-miR-92a-3p as widely involved in platelet reactivity and associated diseases, including CVDs, Alzheimer’s and cerebrovascular diseases, cancer and hypertension. Analysis focused on the identification of the highly regulatory targets shared between those miRNAs identified 43 of them. Best ranked genes associated with overall platelet activity and most susceptible for noncoding regulation were PTEN, PIK3R1, CREB1, APP, and MAPK1. Top targets also strongly associated with CVDs were VEGFA, IGF1, ESR1, BDNF, and PPARG. Top targets associated with other platelet-related diseases including cancer identified in our study were TP53, KRAS, and CCND1. The most affected pathways by top miRNAs and top targets included diseases of signal transduction by Growth Factor Receptors (GDFRs) and second messengers, platelet activation, signaling, and aggregation, signaling by VEGF, MAPK family signaling cascades, and signaling by Interleukins. Terms specific only for platelet-related miRNAs included coronary artery disease, platelet degranulation, and neutrophil degranulation, while for the top platelet-related genes it was Estrogen Signaling Receptor (ESR) mediated signaling, extra-nuclear estrogen signaling, and endometriosis. Our results show the novel features of platelet physiology and may provide a basis for further clinical studies focused on platelet reactivity. They also show in which aspects miRNAs can be promising biomarkers of platelet-related pathological processes.

微小RNA（MicroRNAs）是一类小型非编码RNA，可通过诱导信使RNA（messenger RNA）降解及对基因表达进行转录后抑制，调控细胞各项功能。血小板是循环miRNAs的主要来源，对心血管病理生理学及其他多种疾病具有重要的调控潜力。已有研究证实，miRNAs可调控血小板蛋白的表达水平，进而影响血小板反应性。循环miRNAs可从血浆、血清或全血中被检测到，可作为包括心血管疾病（CVDs）在内的多种疾病的诊断、预后生物标志物，同时也可作为治疗靶点。本研究展示了通过生物信息学分析得到的原创性结果，筛选得到22种与血小板相关的核心miRNAs，包括hsa-miR-320a、hsa-miR-16-5p、hsa-miR-106a-5p、hsa-miR-320b、hsa-miR-15a-5p、hsa-miR-15b-5p、hsa-miR-195-5p及hsa-miR-92a-3p，这些miRNAs广泛参与血小板反应性及相关疾病的调控，涵盖心血管疾病、阿尔茨海默病、脑血管疾病、癌症与高血压。本研究针对上述miRNAs的共同高调控靶点进行分析，共筛选得到43个共同靶点。与整体血小板活性关联最为紧密、且最易受非编码调控的高排名基因为PTEN、PIK3R1、CREB1、APP与MAPK1。同时与心血管疾病强相关的核心靶点包括VEGFA、IGF1、ESR1、BDNF与PPARG。本研究中鉴定得到的、与其他血小板相关疾病（包括癌症）关联的核心靶点为TP53、KRAS与CCND1。受核心miRNAs与核心靶点调控最为显著的通路包括生长因子受体（Growth Factor Receptors，GDFRs）信号转导及第二信使介导的疾病通路、血小板活化、信号转导与聚集通路、血管内皮生长因子（VEGF）信号通路、丝裂原活化蛋白激酶（MAPK）家族信号级联反应通路以及白细胞介素信号通路。仅与血小板相关miRNAs特异性关联的术语包括冠状动脉疾病、血小板脱颗粒与中性粒细胞脱颗粒；而与核心血小板相关基因特异性关联的术语则为雌激素受体（Estrogen Signaling Receptor，ESR）介导的信号通路、核外雌激素信号通路与子宫内膜异位症。本研究结果揭示了血小板生理学的全新特征，可为后续针对血小板反应性的临床研究提供理论基础；同时明确了miRNAs可作为血小板相关病理过程的潜在生物标志物的具体应用方向。