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

Abstract

Background 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. Results 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. Conclusions In summary, SiNPs could accelerate the vascular endothelial dysfunction and prethrombotic state via miR-451a negative regulating the IL6R/STAT/TF signaling pathway. Electronic supplementary material The online version of this article (10.1186/s12989-019-0300-x) contains supplementary material, which is available to authorized users.

Silica nanomaterials induce organ injuries by Ca2+-ROS-initiated disruption of the endothelial barrier and triggering intravascular coagulation

“…Endothelial injury and blood exposure to collagen beneath the endothelium can activate factor XII (Hageman factor) and trigger blood coagulation via the intrinsic coagulation pathway (contact pathway) [41]. Intravascular coagulation may be triggered by endothelial injury/exfoliation, collagen exposure, and initiation of the contact pathway after exposure to SiNPs [42], and/or by changing the levels and activities of coagulant factors, anticoagulants and platelets as previously reported [43][44][45]. Although the pro-coagulation effect of SiNPs was not initially found in the present study, we found impressive intravascular coagulation in multiple organs after in vivo exposure to SiNPs.…”

Amorphous silica nanoparticles accelerated atherosclerotic lesion progression in ApoE−/− mice through endoplasmic reticulum stress-mediated CD36 up-regulation in macrophage

“…We firstly administered Western diet-fed ApoE −/− mice with SiNPs through intratracheal instillation for 12 weeks by mimicking occupational scenario, and UBM was applied to monitor the development and progression of atherosclerosis. Currently, only few studies have reported the vascular effects of NPs through Doppler ultrasound trace [31]. As a result, the data indicated the atherosclerosis model was well established, and SiNPs exposure reduced arterial elasticity, aggravated the arterial stiffness.…”

Amorphous silica nanoparticles accelerated atherosclerotic lesion progression in ApoE-/- mice through endoplasmic reticulum stress-mediated CD36 up-regulation in macrophage

“…We rstly administered Western diet-fed ApoE -/mice with SiNPs or saline through intratracheal instillation for 12 weeks, and UBM was applied to monitor the development and progression of atherosclerosis. Currently, only few studies have reported the vascular effects of NPs through Doppler ultrasound trace [32]. As a result, the data indicated the atherosclerosis model was well established, and SiNPs exposure reduced arterial elasticity, aggravated the arterial stiffness.…”

“…Moreover, a discontinued or fragmented intimal surface was induced by repeated pulmonary exposure of SiNPs, accompanied with endothelial apoptosis [27]. In addition, the ability to induce thrombosis formation may also attribute to the pro-atherogenic potential of SiNPs [32]. However, the underlying mechanisms by which SiNPs in uenced atherogenesis still remains largely unknown.…”