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Amorphous silica nanoparticles trigger vascular endothelial cell injury through apoptosis and autophagy via reactive oxygen species-mediated MAPK/Bcl-2 and PI3K/Akt/mTOR signaling

Authors Guo C, Yang M, Jing L, Wang J, Yu Y, Li Y, Duan J, Zhou X, Li Y, Sun Z

Received 4 May 2016

Accepted for publication 12 July 2016

Published 11 October 2016 Volume 2016:11 Pages 5257—5276

DOI https://doi.org/10.2147/IJN.S112030

Checked for plagiarism Yes

Review by Single-blind

Peer reviewers approved by Dr Yashdeep Phanse

Peer reviewer comments 2

Editor who approved publication: Dr Lei Yang


Caixia Guo,1,2 Man Yang,2,3 Li Jing,2,3 Ji Wang,2,3 Yang Yu,2,3 Yang Li,2,3 Junchao Duan,2,3 Xianqing Zhou,2,3 Yanbo Li,2,3 Zhiwei Sun2,3

1Department of Occupational and Environmental Health, School of Public Health, 2Beijing Key Laboratory of Environmental Toxicology, 3Department of Toxicology and Sanitary Chemistry, School of Public Health, Capital Medical University, Beijing, People’s Republic of China

Abstract:
Environmental exposure to silica nanoparticles (SiNPs) is inevitable due to their widespread application in industrial, commercial, and biomedical fields. In recent years, most investigators focus on the evaluation of cardiovascular effects of SiNPs in vivo and in vitro. Endothelial injury and dysfunction is now hypothesized to be a dominant mechanism in the development of cardiovascular diseases. This study aimed to explore interaction of SiNPs with endothelial cells, and extensively investigate the exact effects of reactive oxygen species (ROS) on the signaling molecules and cytotoxicity involved in SiNPs-induced endothelial injury. Significant induction of cytotoxicity as well as oxidative stress, apoptosis, and autophagy was observed in human umbilical vein endothelial cells following the SiNPs exposure (P<0.05). The oxidative stress was induced by ROS generation, leading to redox imbalance and lipid peroxidation. SiNPs induced mitochondrial dysfunction, characterized by membrane potential collapse, and elevated Bax and declined bcl-2 expression, ultimately leading to apoptosis, and also increased number of autophagosomes and autophagy marker proteins, such as LC3 and p62. Phosphorylated ERK, PI3K, Akt, and mTOR were significantly decreased, but phosphorylated JNK and p38 MAPK were increased in SiNPs-exposed endothelial cells. In contrast, all of these stimulation phenomena were effectively inhibited by N-acetylcysteine. The N-acetylcysteine supplement attenuated SiNPs-induced endothelial toxicity through inhibition of apoptosis and autophagy via MAPK/Bcl-2 and PI3K/Akt/mTOR signaling, as well as suppression of intracellular ROS property via activating antioxidant enzyme and Nrf2 signaling. In summary, the results demonstrated that SiNPs triggered autophagy and apoptosis via ROS-mediated MAPK/Bcl-2 and PI3K/Akt/mTOR signaling in endothelial cells, and subsequently disturbed the endothelial homeostasis and impaired endothelium. Our findings may provide experimental evidence and explanation for cardiovascular diseases triggered by SiNPs. Furthermore, results hint that the application of antioxidant may provide a novel way for safer use of nanomaterials.

Keywords: nanoparticle, cytotoxicity, mechanism, oxidative stress

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