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

Abstract Background Given the prominent cardiovascular effects of nanosized particulate matter in air pollution, our limited understanding of the potential cardiovascular effects of engineered nanoparticles, in particular, is a pressing concern. Silica nanoparticles (SiNPs) are among the most widely manufactured and used nanoparticles. However, the interaction between SiNPs exposure and atherosclerosis, and the underlying mechanisms still remain unknown. Results Ultrasound microscopy showed a significant increase of pulse wave velocity (PWV) in ApoE−/− mice fed by a Western diet after SiNPs exposure via intratracheal instillation compared to the control mice. Histopathological investigation reflected a greater plaque burden with higher lipid load in the aortic root of SiNPs-exposed ApoE−/− mice. When compared to the control, serum levels of total triglycerides (TG) and low-density lipoprotein cholesterol (LDL-C) were significantly elevated after SiNPs exposure. Moreover, intensified macrophage infiltration and endoplasmic reticulum (ER) stress were occurred in plaques after SiNPs exposure, as evidenced by the upregulated CD68 and Bip, CHOP levels. 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 could greatly alleviate SiNPs-induced macrophage lipid accumulation, and reverse the elevated CD36 expression by SiNPs. Conclusions Our results firstly revealed the acceleratory effect of SiNPs on atherosclerosis in ApoE−/− mice. SiNPs aggravated the plaque load in the aorta of mice, promoted macrophage infiltration and ER stress inside the lesion, alongside with the exacerbated arterial stiffness and dyslipidemia. Further, ER stress-mediated CD36 upregulation contributed to the formation of macrophage-derived foam cell caused by SiNPs, ultimately contributing to the progression of atherosclerotic plaque.