Silica nanoparticles trigger the vascular endothelial dysfunction and prethrombotic state via miR-451 directly regulating the IL6R signaling pathway

Lin Feng,Xiaozhe Yang,Shuang Liang,Junchao Duan,Qing Xu,Mark R Miller,Zhiwei Sun

doi:10.1186/s12989-019-0300-x

Abstract

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

Highlights

Safety evaluation is a prerequisite for nanomaterials in a wide range of fields, including chemical industries, medicine or food sciences
The cardiac output was decreasing significantly from 108 mL/min to 83 mL/min in SiNPs-treated group compared with control
For the first time, this study demonstrated that SiNPs could trigger the vascular endothelial dysfunction and a prethrombotic state via miR-451a negative regulating the IL6R/STAT/Tissue factor (TF) signaling pathway

Summary

Introduction

Safety evaluation is a prerequisite for nanomaterials in a wide range of fields, including chemical industries, medicine or food sciences. 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. Silica nanoparticles (SiNPs) were widely used in nanomedicine fields, including diagnosis, drug delivery systems, gene therapy vector and bioimaging [1]. The Virchow Theory which is widely acceptable for thrombus formation emphasizes that the thrombosis is closely associated with vascular endothelial injury, hemodynamic change and hypercoagulation [7]. A 10 μg/m3 elevation in particulate matter was associated with a 70% increase in deep vein thrombosis risk [9]. The underlying molecular mechanisms of SiNPs on thrombus formation remain unclear

Objectives

Methods

Results

Discussion

Conclusion