Silica nanoparticles promote oxLDL-induced macrophage lipid accumulation and apoptosis via endoplasmic reticulum stress signaling.

Oxidized low-density lipoprotein (oxLDL), a marker of hyperlipidemia, plays a pivotal role in the development of atherosclerosis through the induction of macrophage-derived foam cell formation and thereafter apoptosis. Previous studies have indicated that silica nanoparticle (SiNPs) may exert a proatherogenic role, which could induce endothelial dysfunction, and monocytes infiltration. However, little is known about SiNPs' effects on macrophage-derived foam cell formation and apoptosis in the pathogenesis of atherosclerosis. In this study, we investigated the effects of SiNPs and oxLDL coexposure on macrophage-derived lipid metabolism, foam cell and apoptosis by using Raw264.7 cells. As a result, SiNPs enhanced cytotoxicity, apoptosis, and lipid accumulation upon oxLDL stimulation. Furthermore, quantitative determination of the expression levels of genes involved in cholesterol influx or efflux showed significantly up-regulated expressions of CD36 and SRA, whereas down-regulated expressions of ATP-binding cassette A1 (ABCA1), ABCG1, and SRB1 in oxLDL-treated macrophages, especially upon the co-exposure with SiNPs. It indicated that SiNPs promoted lipid accumulation in macrophage cells through not only facilitating cholesterol influx but also inhibiting cholesterol efflux. Endoplasmic reticulum (ER) is specialized for the production, modification, even trafficking of lipids. Interestingly, ER response was triggered upon oxLDL treatment, while SiNPs coexposure augmented the ER stress. Taken together, our results revealed that SiNPs promoted oxLDL-induced macrophage foam cell formation and apoptosis, which may be mediated by ER stress signaling. Thus we propose future researches needed for a better understanding of NPs' toxicity and their interactions with various pathophysiological conditions.