Silica nanoparticles induce autophagy and endothelial dysfunction via the PI3K/Akt/mTOR signaling pathway

Abstract

Junchao Duan,1,2 Yongbo Yu,1,2 Yang Yu,1,2 Yang Li,1,2 Ji Wang,1,2 Weijia Geng,1,2 Lizhen Jiang,1,2 Qiuling Li,1,2 Xianqing Zhou,1,2 Zhiwei Sun1,2 1School of Public Health, Capital Medical University, Beijing, 2Beijing Key Laboratory of Environmental Toxicology, Capital Medical University, Beijing, People’s Republic of China Abstract: Although nanoparticles have a great potential for biomedical applications, there is still a lack of a correlative safety evaluation on the cardiovascular system. This study is aimed to clarify the biological behavior and influence of silica nanoparticles (Nano-SiO2) on endothelial cell function. The results showed that the Nano-SiO2 were internalized into endothelial cells in a dose-dependent manner. Monodansylcadaverine staining, autophagic ultrastructural observation, and LC3-I/LC3-II conversion were employed to verify autophagy activation induced by Nano-SiO2, and the whole autophagic process was also observed in endothelial cells. In addition, the level of nitric oxide (NO), the activities of NO synthase (NOS) and endothelial (e)NOS were significantly decreased in a dose-dependent way, while the activity of inducible (i)NOS was markedly increased. The expression of C-reactive protein, as well as the production of proinflammatory cytokines (tumor necrosis factor α, interleukin [IL]-1β, and IL-6) were significantly elevated. Moreover, Nano-SiO2 had an inhibitory effect on the phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR) signaling pathway. Our findings demonstrated that Nano-SiO2 could disturb the NO/NOS system, induce inflammatory response, activate autophagy, and eventually lead to endothelial dysfunction via the PI3K/Akt/mTOR pathway. This indicates that exposure to Nano-SiO2 is a potential risk factor for cardiovascular diseases. Keywords: silica nanoparticles, endothelial dysfunction, autophagy, nitric oxide, inflammation