title: Role of Cyt-C/caspases-9,3, Bax/Bcl-2 and the FAS death receptor pathway in apoptosis induced by zinc oxide nanoparticles in human aortic endothelial cells and the protective effect by alpha-lipoic acid.
abstract: Zinc oxide nanoparticles (ZnO NPs) are widely used in a variety of products used in daily life. However, their impact on human health has not been completely elucidated. This study was designed to investigate the cytotoxicity associated with ZnO NPs, the role of dissolution in the toxicity of ZnO NPs, the molecular mechanisms and mode of cell death induced by ZnO NPs in human aortic endothelial cells (HAECs), and the protective effects of the antioxidant alpha-lipoic acid (LA). ZnO NPs significantly reduced cell viability in a dose- and time-dependent manner, resulted in intracellular oxidative stress and cell membrane leakage when treated with doses of 8-50 μg/mL for 12 and 24 h in HAECs. The toxicity was produced by undissolved ZnO NPs but not dissolved Zn(2+) and metal impurities. Exposure to ZnO NPs was found to induce apoptosis at 12 h and necrosis after 24 h. Apoptosis was confirmed using reactive oxygen species that triggered a decrease in mitochondria membrane potential, increase in Cyt-C release, activation of caspases 3 and caspases9 and increase in the ratio of Bax/Bcl-2. Futhermore, ZnO NPs could activate the Fas death receptor pathway. In addition, the antioxidant LA was able to protect HAECs from apoptosis induced by ZnO NPs.
authors.affiliation: Public Health College, Harbin Medical University, Harbin, China; First Affiliated Hospital, Harbin Medical University, Harbin, China.
authors.forename: Shuhang
authors.initials: S
authors.lastname: Liang
authors.affiliation: Public Health College, Harbin Medical University, Harbin, China.
authors.forename: Kuo
authors.initials: K
authors.lastname: Sun
authors.affiliation: Public Health College, Harbin Medical University, Harbin, China.
authors.forename: Yue
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Public Health College, Harbin Medical University, Harbin, China. Electronic address: dong.shuying@163.com.
authors.forename: Shuying
authors.initials: S
authors.lastname: Dong
authors.affiliation: Public Health College, Harbin Medical University, Harbin, China.
authors.forename: Cheng
authors.initials: C
authors.lastname: Wang
authors.affiliation: First Affiliated Hospital, Harbin Medical University, Harbin, China.
authors.forename: LianXin
authors.initials: L
authors.lastname: Liu
authors.affiliation: Public Health College, Harbin Medical University, Harbin, China.
authors.forename: YongHui
authors.initials: Y
authors.lastname: Wu
mesh_terms: D000590:Amino Acid Chloromethyl Ketones; D001011:Aorta / Q000166:cytology; D017209:Apoptosis / Q000187:drug effects*; D053148:Caspase 3 / Q000378:metabolism; D053453:Caspase 9 / Q000378:metabolism; D020169:Caspases / Q000378:metabolism*; D053144:Cell Nucleus Shape / Q000187:drug effects; D048430:Cell Shape / Q000187:drug effects; D016572:Cyclosporine / Q000494:pharmacology; D045304:Cytochromes c / Q000378:metabolism*; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism* / Q000648:ultrastructure; D006801:Humans; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D053758:Nanoparticles / Q000737:chemistry / Q000648:ultrastructure; D020011:Protective Agents / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D012995:Solubility; D013347:Subcellular Fractions / Q000378:metabolism; D008063:Thioctic Acid / Q000494:pharmacology*; D015034:Zinc Oxide / Q000494:pharmacology*; D051028:bcl-2-Associated X Protein / Q000378:metabolism*; D019014:fas Receptor / Q000378:metabolism*
chemical_list: D000590:Amino Acid Chloromethyl Ketones; D020011:Protective Agents; D017382:Reactive Oxygen Species; D051028:bcl-2-Associated X Protein; C096713:benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone; D019014:fas Receptor; D008063:Thioctic Acid; D016572:Cyclosporine; D045304:Cytochromes c; D053148:Caspase 3; D053453:Caspase 9; D020169:Caspases; D015034:Zinc Oxide
keywords: Alpha-lipoic acid; Bax/Bcl-2; Cyt-C/caspases-9,3; Fas; ZnO NPs