Silica nanoparticles trigger the vascular endothelial dysfunction and prethrombotic state via miR-451 directly regulating the IL6R signaling pathway
Silica nanoparticles trigger the vascular endothelial dysfunction and prethrombotic state via miR-451 directly regulating the IL6R signaling pathway
复制标题
二氧化硅纳米颗粒通过 miR-451 直接调节 IL6R 信号通路触发血管内皮功能障碍和血栓前状态
DOI：
10.1186/s12989-019-0300-x
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发表时间：
2019-04-11
影响因子：
10
通讯作者：
Sun, Zhiwei
中科院分区：
文献类型：
--
作者：
Feng, Lin;Yang, Xiaozhe;Sun, Zhiwei
背景纳米材料的安全性评价是纳米材料广泛应用于化工、医药、食品等领域的先决条件。以前，我们已经证明SiNPs可以在体内触发血栓形成效应，但其潜在机制仍然未知。本研究旨在探讨和验证miR-451 a在SiNPs诱导的血管内皮功能障碍和血栓前状态中的作用。组织学和超微结构分析表明SiNPs可诱导血管内皮损伤。此外，SiNPs触发的主动脉弓组织MDA表达水平升高，SOD和GSH-Px活性降低，血清中iNOS释放和eNOS下降。免疫组化结果显示，TF和PECAM-1的阳性染色在SiNPs诱导下呈剂量依赖性增加。SiNPs通过缩短TT、PT和APTT激活凝血功能，并显著升高FIB。凝血因子（TF、FXa和vWF）和PLT数量增加，而抗凝因子（ATIII、TFPI和t-PA）水平降低。基因芯片分析显示，下调的miR-451 a可靶向IL 6 R基因表达，进而激活SiNPs触发的JAK/STAT信号通路。双荧光素酶报告基因检测证实了miR-451 a与IL 6 R之间的直接靶向关系。miR-451 a的化学模拟物可抑制SiNPs诱导的IL 6 R/STAT/TF信号通路的表达，而miR-451 a的抑制剂可增强IL 6 R/STAT/TF信号通路的激活。
BackgroundSafety evaluation is a prerequisite for nanomaterials in a wide range of fields, including chemical industries, medicine or food sciences. Previously, we had demonstrated that SiNPs could trigger the thrombotic effects in vivo, but the underlying mechanisms remain unknown. This study was aimed to explore and verify the role of miR-451a on SiNPs-induced vascular endothelial dysfunction and pre-thrombotic state.ResultsThe color doppler ultrasound results showed that SiNPs had the inhibitory effects on aorta velocity and cardiac output. The histological and ultrastructural analysis manifested that SiNPs could induce the vascular endothelial damage. In addition, the expression level of MDA was elevated while the activity of SOD and GSH-Px were decreased in aortic arch triggered by SiNPs, accompanied with the release of iNOS and decline of eNOS in blood serum. The immunohistochemistry results showed that the positive staining of TF and PECAM-1 were elevated in a dose-dependent manner induced by SiNPs. The activation of coagulation function occurred via shortened TT, PT and APTT while the FIB was elevated markedly induced by SiNPs. Coagulant factors (TF, FXa and vWF) and PLT numbers were increased whereas the levels of anticoagulant factors (ATIII, TFPI and t-PA) were decreased. Microarray analysis showed that the down-regulated miR-451a could target the gene expression ofIL6R, which further activated the JAK/STAT signaling pathway triggered by SiNPs. Dual-luciferase reporter gene assay confirmed the directly target relationship between miR-451a and IL6R. Additionally, the chemical mimics of miR-451a led to attenuate the expression of IL6R/STAT/TF signaling pathway in vitro and in vivo induced by SiNPs, while the inhibitor of miR-451a enhanced the activation of IL6R/STAT/TF signaling pathway.ConclusionsIn summary, SiNPs could accelerate the vascular endothelial dysfunction and prethrombotic state via miR-451a negative regulating the IL6R/STAT/TF signaling pathway.