Reyes-García Ascensión María de Los, Aroca Alejandra, Arroyo Ana Belén, García-Barbera Nuria, Vicente Vicente, González-Conejero Rocío, Martínez Constantino
Department of Hematology and Medical Oncology, Morales Meseguer University Hospital, Centro Regional de Hemodonación, University of Murcia, Instituto Murciano de Investigación Biosanitaria (IMIB-Arrixaca), 30003 Murcia, Spain.
Biomed Rep. 2019 Mar;10(3):195-201. doi: 10.3892/br.2019.1187. Epub 2019 Jan 23.
Neutrophil extracellular traps (NETs) represent an important link between inflammation and thrombosis. Here, the present study aimed to investigate the influence of the NET components, DNA and histone H4, on hemostatic gene expression. A further aim was to confirm the influence of H4 on the expression of tissue factor (TF) and investigate a potential effect of DNA, and to test the involvement of miR-17/92 and its paralog miR-106b-25 in this regulation. In HepG2 cells, the mRNA levels of and , which are crucial in the activation of the coagulation cascade, and of (encoding α2-antiplasmin) were significantly upregulated by DNA and H4; while the mRNA levels of , which is essential for thrombin generation of , a cofactor of protein C that also has the ability to inhibit the factor X activation pathway, and of (encoding antithrombin, the main endogenous anticoagulant) were significantly upregulated only by H4. H4 and DNA also provoked an increase in hepatocyte nuclear factor 4α () mRNA expression that could be responsible for the increase in the expression of certain coagulant factors. In THP-1 cells, it was also demonstrated that H4 caused an increase in mRNA while decreasing several of the microRNAs (miRNA/miRs) of the cluster miR-17/92, which may in part explain the increase in the expression of . The present results suggest the ability of NET components to alter the hemostatic balance and a possible involvement of HNF4α and miRNAs in this regulation.
中性粒细胞胞外诱捕网（NETs）是炎症与血栓形成之间的重要联系。在此，本研究旨在探究NET成分DNA和组蛋白H4对止血基因表达的影响。另一个目的是证实H4对组织因子（TF）表达的影响，并研究DNA的潜在作用，以及测试miR-17/92及其旁系同源物miR-106b-25在该调节过程中的参与情况。在HepG2细胞中，凝血级联激活中起关键作用的凝血酶原（F2）和纤维蛋白原（FGA）以及α2-抗纤溶酶（SERPINA3）的mRNA水平被DNA和H4显著上调；而蛋白C辅因子凝血酶原激活物（F10）（其也具有抑制因子X激活途径的能力）生成凝血酶所必需的组织因子途径抑制物（TFPI）以及抗凝血酶（SERPINC1）（主要内源性抗凝剂）的mRNA水平仅被H4显著上调。H4和DNA还引发了肝细胞核因子4α（HNF4α）mRNA表达增加，这可能是某些凝血因子表达增加的原因。在THP-1细胞中，还证实H4导致组织因子（TF）mRNA增加，同时降低了miR-17/92簇的几种微小RNA（miRNA/miRs），这可能部分解释了组织因子（TF）表达的增加。目前结果表明NET成分有改变止血平衡的能力，并且HNF4α和miRNAs可能参与了这一调节过程。
