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

Abstract

Background The biosafety concern of silica nanoparticles (SiNPs) is rapidly expanding alongside with its mass production and extensive applications. The cardiovascular effects of SiNPs exposure have been gradually confirmed, however, the interaction between SiNPs exposure and atherosclerosis, and the underlying mechanisms still remain unknown. Thereby, this study aimed to explore the effects of SiNPs on the progression of atherosclerosis, and to investigate related mechanisms. Results We firstly investigated the in vivo effects of SiNPs exposure on atherosclerosis via intratracheal instillation of ApoE−/− mice fed a Western diet. Ultrasound microscopy showed a significant increase of pulse wave velocity (PWV) compared to the control group, and the histopathological investigation reflected a greater plaque burden in the aortic root of SiNPs-exposed ApoE−/− mice. Compared to the control group, the serum levels of total triglycerides (TG) and low-density lipoprotein cholesterol (LDL-C) were elevated after SiNPs exposure. Moreover, intensified macrophage infiltration and endoplasmic reticulum (ER) stress was occurred in plaques after SiNPs exposure, as evidenced by the upregulated CD68 and CHOP expressions. Further in vitro, SiNPs was confirmed to activate ER stress and induce lipid accumulation in mouse macrophage, RAW264.7. Mechanistic analyses showed that 4-PBA (a classic ER stress inhibitor) pretreatment greatly alleviated SiNPs-induced macrophage lipid accumulation, and reversed the elevated CD36 expression induced by SiNPs. Conclusions Our results firstly revealed the acceleratory effect of SiNPs on the progression of atherosclerosis in ApoE−/− mice, which was related to lipid accumulation caused by ER stress-mediated upregulation of CD36 expression in macrophage. Graphical abstract

Influences of Unmodified and Carboxylated Carbon Nanotubes on Lipid Profiles in THP-1 Macrophages: A Lipidomics Study

“…It has been shown before that unmodified and carboxylated MWCNTs induced lipid accumulation in THP-1 macrophages 21 and human vascular smooth muscle cells 25 to a similar extent, but unmodified MWCNTs were more potent than carboxylated MWCNTs to induce lipid accumulation in HepG2 hepatocytes, 26 indicating that the influence of carboxylation on MWCNT-induced lipid accumulation is likely to be cell type dependent. Previous studies showed that SiO 2 NPs, 28,29 ZnO NPs, 30 and carbon black NPs 31 induced lipid accumulation in macrophages, but in contrast, graphene oxide 32 and Ag NPs 33 reduced lipid species in macrophages. These results indicated that NMs altered lipid levels in macrophages in a manner dependent on the compositions of NMs.…”

“…We then investigated ER stress-mediated lipid metabolism because it has been suggested that the toxicity of NMs is related with the induction of ER stress. 37,38 In macrophages, MWCNTs 21,39 and SiO 2 NPs 29,40 have been shown to induce lipid accumulation by inducing ER stress leading to the up-regulation of scavenger receptors and/or de novo lipogenesis. Meanwhile, van der Valk et al reported that liposomal NPs loaded with prednisolone induced lipotoxicity to macrophages through ER stress.…”

PINK1/TAX1BP1-directed mitophagy attenuates vascular endothelial injury induced by copper oxide nanoparticles

“…Exposure to combustion-derived NPs impairs vascular physiological functions and inhibits arterial vasodilatation both in pre-clinical (rat model) and clinical model [ 20 ]. Pulmonary exposure to engineered NPs results in oxidative stress and inflammation, consequently contributes to the progression of atherosclerosis [ 21 – 23 ]. Vascular endothelial cells cover the inner surface of all blood vessels and serve as a regulatory hub of systemic circulation [ 24 ].…”

Myocardial toxicity induced by silica nanoparticles in a transcriptome profile

“…Accumulative experimental evidence has demonstrated the extra-pulmonary translocation of inhaled nanoparticles (NPs), 5,6 which could pass through the air-blood barrier into blood circulation, 7,8 distribute into multi-organs (e.g., liver, heart, and kidneys), and lead to systemic toxicity. [9][10][11] Interestingly, the direct penetration of NPs into the human heart has been recently reported. Hence, the evaluation of NPs-elicited cardiotoxicity as a public health issue needs to be solved urgently.…”

“…, liver, heart, and kidneys), and lead to systemic toxicity. 9–11 Interestingly, the direct penetration of NPs into the human heart has been recently reported. Hence, the evaluation of NPs-elicited cardiotoxicity as a public health issue needs to be solved urgently.…”