title: Toxic effect of silica nanoparticles on endothelial cells through DNA damage response via Chk1-dependent G2/M checkpoint.
abstract: Silica nanoparticles have become promising carriers for drug delivery or gene therapy. Endothelial cells could be directly exposed to silica nanoparticles by intravenous administration. However, the underlying toxic effect mechanisms of silica nanoparticles on endothelial cells are still poorly understood. In order to clarify the cytotoxicity of endothelial cells induced by silica nanoparticles and its mechanisms, cellular morphology, cell viability and lactate dehydrogenase (LDH) release were observed in human umbilical vein endothelial cells (HUVECs) as assessing cytotoxicity, resulted in a dose- and time- dependent manner. Silica nanoparticles-induced reactive oxygen species (ROS) generation caused oxidative damage followed by the production of malondialdehyde (MDA) as well as the inhibition of superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px). Both necrosis and apoptosis were increased significantly after 24 h exposure. The mitochondrial membrane potential (MMP) decreased obviously in a dose-dependent manner. The degree of DNA damage including the percentage of tail DNA, tail length and Olive tail moment (OTM) were markedly aggravated. Silica nanoparticles also induced G2/M arrest through the upregulation of Chk1 and the downregulation of Cdc25C, cyclin B1/Cdc2. In summary, our data indicated that the toxic effect mechanisms of silica nanoparticles on endothelial cells was through DNA damage response (DDR) via Chk1-dependent G2/M checkpoint signaling pathway, suggesting that exposure to silica nanoparticles could be a potential hazards for the development of cardiovascular diseases.
authors.affiliation: School of Public Health, Capital Medical University, Beijing, PR China.
authors.forename: Junchao
authors.initials: J
authors.lastname: Duan
authors.forename: Yongbo
authors.initials: Y
authors.lastname: Yu
authors.forename: Yang
authors.initials: Y
authors.lastname: Li
authors.forename: Yang
authors.initials: Y
authors.lastname: Yu
authors.forename: Yanbo
authors.initials: Y
authors.lastname: Li
authors.forename: Xianqing
authors.initials: X
authors.lastname: Zhou
authors.forename: Peili
authors.initials: P
authors.lastname: Huang
authors.forename: Zhiwei
authors.initials: Z
authors.lastname: Sun
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D000071877:Checkpoint Kinase 1; D020552:Comet Assay; D004249:DNA Damage; D004705:Endocytosis / Q000187:drug effects; D005434:Flow Cytometry; D059565:G2 Phase Cell Cycle Checkpoints / Q000187:drug effects*; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology*; D006801:Humans; D057446:Hydrodynamics; D042541:Intracellular Space / Q000187:drug effects / Q000378:metabolism; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D053758:Nanoparticles / Q000737:chemistry / Q000633:toxicity* / Q000648:ultrastructure; D009336:Necrosis; D018384:Oxidative Stress / Q000187:drug effects; D010316:Particle Size; D011494:Protein Kinases / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism; D012822:Silicon Dioxide / Q000633:toxicity*; D055672:Static Electricity; D013347:Subcellular Fractions / Q000187:drug effects / Q000378:metabolism
chemical_list: D017382:Reactive Oxygen Species; D012822:Silicon Dioxide; D011494:Protein Kinases; C000605867:CHEK1 protein, human; D000071877:Checkpoint Kinase 1