Safety 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. The 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 of IL6R, 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. In summary, SiNPs could accelerate the vascular endothelial dysfunction and prethrombotic state via miR-451a negative regulating the IL6R/STAT/TF signaling pathway.

中文翻译：

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二氧化硅纳米粒子通过直接调节 IL6R 信号通路的 miR-451 触发血管内皮功能障碍和血栓前状态

安全性评估是纳米材料在化学工业、医学或食品科学等广泛领域中的先决条件。以前，我们已经证明 SiNPs 可以在体内触发血栓形成作用，但潜在的机制仍然未知。本研究旨在探索和验证 miR-451a 在 SiNPs 诱导的血管内皮功能障碍和血栓前状态中的作用。彩色多普勒超声结果表明，SiNPs 对主动脉速度和心输出量有抑制作用。组织学和超微结构分析表明，SiNPs 可以诱导血管内皮损伤。此外，在SiNPs触发的主动脉弓中，MDA的表达水平升高，而SOD和GSH-Px的活性降低，伴随着血清中 iNOS 的释放和 eNOS 的下降。免疫组化结果表明，SiNPs 诱导的 TF 和 PECAM-1 阳性染色呈剂量依赖性升高。凝血功能的激活通过缩短的 TT、PT 和 APTT 发生，而 FIB 则由 SiNPs 诱导显着升高。凝血因子（TF、FXa 和 vWF）和 PLT 数量增加，而抗凝血因子（ATIII、TFPI 和 t-PA）水平降低。微阵列分析表明，下调的 miR-451a 可以靶向 IL6R 的基因表达，从而进一步激活由 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-451a 和 IL6R 之间的直接靶标关系。此外，miR-451a的化学模拟物导致SiNPs诱导的体外和体内IL6R/STAT/TF信号通路的表达减弱，而miR-451a的抑制剂增强了IL6R/STAT/TF信号通路的激活。总之，SiNPs 可以通过 miR-451a 负调节 IL6R/STAT/TF 信号通路加速血管内皮功能障碍和血栓前状态。