title: Silica nanoparticles induce oxidative stress, inflammation, and endothelial dysfunction in vitro via activation of the MAPK/Nrf2 pathway and nuclear factor-κB signaling.
abstract: Despite the widespread application of silica nanoparticles (SiNPs) in industrial, commercial, and biomedical fields, their response to human cells has not been fully elucidated. Overall, little is known about the toxicological effects of SiNPs on the cardiovascular system. In this study, SiNPs with a 58 nm diameter were used to study their interaction with human umbilical vein endothelial cells (HUVECs). Dose- and time-dependent decrease in cell viability and damage on cell plasma-membrane integrity showed the cytotoxic potential of the SiNPs. SiNPs were found to induce oxidative stress, as evidenced by the significant elevation of reactive oxygen species generation and malondialdehyde production and downregulated activity in glutathione peroxidase. SiNPs also stimulated release of cytoprotective nitric oxide (NO) and upregulated inducible nitric oxide synthase (NOS) messenger ribonucleic acid, while downregulating endothelial NOS and ET-1 messenger ribonucleic acid, suggesting that SiNPs disturbed the NO/NOS system. SiNP-induced oxidative stress and NO/NOS imbalance resulted in endothelial dysfunction. SiNPs induced inflammation characterized by the upregulation of key inflammatory mediators, including IL-1β, IL-6, IL-8, TNFα, ICAM-1, VCAM-1, and MCP-1. In addition, SiNPs triggered the activation of the Nrf2-mediated antioxidant system, as evidenced by the induction of nuclear factor-κB and MAPK pathway activation. Our findings demonstrated that SiNPs could induce oxidative stress, inflammation, and NO/NOS system imbalance, and eventually lead to endothelial dysfunction via activation of the MAPK/Nrf2 pathway and nuclear factor-κB signaling. This study indicated a potential deleterious effect of SiNPs on the vascular endothelium, which warrants more careful assessment of SiNPs before their application.
authors.affiliation: School of Public Health, Capital Medical University, Beijing, People's Republic of China ; Beijing Key Laboratory of Environmental Toxicology, Capital Medical University, Beijing, People's Republic of China.
authors.forename: Caixia
authors.initials: C
authors.lastname: Guo
authors.affiliation: School of Public Health, Capital Medical University, Beijing, People's Republic of China ; Beijing Key Laboratory of Environmental Toxicology, Capital Medical University, Beijing, People's Republic of China.
authors.forename: Yinye
authors.initials: Y
authors.lastname: Xia
authors.affiliation: School of Public Health, Capital Medical University, Beijing, People's Republic of China ; Beijing Key Laboratory of Environmental Toxicology, Capital Medical University, Beijing, People's Republic of China.
authors.forename: Piye
authors.initials: P
authors.lastname: Niu
authors.affiliation: School of Public Health, Capital Medical University, Beijing, People's Republic of China ; Beijing Key Laboratory of Environmental Toxicology, Capital Medical University, Beijing, People's Republic of China.
authors.forename: Lizhen
authors.initials: L
authors.lastname: Jiang
authors.affiliation: School of Public Health, Capital Medical University, Beijing, People's Republic of China ; Beijing Key Laboratory of Environmental Toxicology, Capital Medical University, Beijing, People's Republic of China.
authors.forename: Junchao
authors.initials: J
authors.lastname: Duan
authors.affiliation: School of Public Health, Capital Medical University, Beijing, People's Republic of China ; Beijing Key Laboratory of Environmental Toxicology, Capital Medical University, Beijing, People's Republic of China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Yu
authors.affiliation: School of Public Health, Capital Medical University, Beijing, People's Republic of China ; Beijing Key Laboratory of Environmental Toxicology, Capital Medical University, Beijing, People's Republic of China.
authors.forename: Xianqing
authors.initials: X
authors.lastname: Zhou
authors.affiliation: School of Public Health, Capital Medical University, Beijing, People's Republic of China ; Beijing Key Laboratory of Environmental Toxicology, Capital Medical University, Beijing, People's Republic of China.
authors.forename: Yanbo
authors.initials: Y
authors.lastname: Li
authors.affiliation: School of Public Health, Capital Medical University, Beijing, People's Republic of China ; Beijing Key Laboratory of Environmental Toxicology, Capital Medical University, Beijing, People's Republic of China.
authors.forename: Zhiwei
authors.initials: Z
authors.lastname: Sun
mesh_terms: D002460:Cell Line; D004730:Endothelium, Vascular / Q000187:drug effects*; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D007249:Inflammation / Q000139:chemically induced*; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism*; D051267:NF-E2-Related Factor 2 / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism*; D053758:Nanoparticles / Q000737:chemistry / Q000633:toxicity; D018384:Oxidative Stress / Q000187:drug effects*; D012822:Silicon Dioxide / Q000737:chemistry / Q000633:toxicity
chemical_list: D051267:NF-E2-Related Factor 2; D016328:NF-kappa B; D012822:Silicon Dioxide; D020929:Mitogen-Activated Protein Kinase Kinases
keywords: MAPK; NF-κB; Nrf2; endothelium; oxidative stress; silica nanoparticle