title: Zinc oxide nanoparticles-induced intercellular adhesion molecule 1 expression requires Rac1/Cdc42, mixed lineage kinase 3, and c-Jun N-terminal kinase activation in endothelial cells.
abstract: The explosive development of nanotechnology has caused an increase in unintended biohazards in humans and in the ecosystem. Similar to particulate matter, nanoparticles (NPs) are strongly correlated with the increase in incidences of cardiovascular diseases, yet the mechanisms behind this correlation remain unclear. Within the testing concentrations of 0.1-10 μg/ml, which did not cause a marked drop in cell viability, zinc oxide NPs (ZnO-NPs) induced intercellular adhesion molecule-1 (ICAM-1) messenger RNA, and protein expression in both concentration- and time-dependent manner in treated human umbilical vein endothelial cells (HUVECs). ZnO-NPs treatment cause the activation of Ras-related C3 botulinum toxin substrate 1 (Rac1)/cell division control protein 42 homolog (Cdc42) and protein accumulation of mixed lineage kinase 3 (MLK3), followed by c-Jun N-terminal kinase (JNK) and transcription factor c-Jun activation. Induction of ICAM-1 and phosphorylation of JNK and c-Jun could be inhibited by either JNK inhibitor SP600125 or Rac guanosine triphosphatase inhibitor NSC23766 pretreatment. In addition, pretreatment with NSC23766 significantly reduced MLK3 accumulation, suggesting the involvement of Rac1/Cdc42-MLK3-JNK-c-Jun signaling in the regulation of ZnO-NPs-induced ICAM-1 expression, whereas these signaling factors were not activated in zinc oxide microparticles (ZnO-MPs)-treated HUVECs. The increase of ICAM-1 expression on ZnO-NPs-treated HUVECs enables leukocytes to adhere and has been identified as an indicator of vascular inflammation. Our data are essential for safety evaluation of the clinical usage of ZnO-NPs in daily supplements, cosmetics, and biomedicines.
authors.affiliation: Institute of Toxicology, College of Medicine, National Taiwan University, Taipei, Taiwan.
authors.forename: Ching-Hao
authors.initials: CH
authors.lastname: Li
authors.forename: Po-Lin
authors.initials: PL
authors.lastname: Liao
authors.forename: Ming-Kwang
authors.initials: MK
authors.lastname: Shyu
authors.forename: Chen-Wei
authors.initials: CW
authors.lastname: Liu
authors.forename: Chen-Chieh
authors.initials: CC
authors.lastname: Kao
authors.forename: Shih-Hsuan
authors.initials: SH
authors.lastname: Huang
authors.forename: Yu-Wen
authors.initials: YW
authors.lastname: Cheng
authors.forename: Jaw-Jou
authors.initials: JJ
authors.lastname: Kang
mesh_terms: D000818:Animals; D001013:Aorta, Thoracic / Q000166:cytology / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004705:Endocytosis; D042783:Endothelial Cells / Q000187:drug effects* / Q000378:metabolism / Q000648:ultrastructure; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000235:genetics / Q000378:metabolism*; D020930:MAP Kinase Kinase Kinases / Q000378:metabolism*; D020935:MAP Kinase Signaling System / Q000187:drug effects; D053768:Metal Nanoparticles / Q000009:adverse effects* / Q000737:chemistry / Q000648:ultrastructure; D051379:Mice; D008822:Mice, Transgenic; D010316:Particle Size; D012333:RNA, Messenger / Q000378:metabolism; D015034:Zinc Oxide / Q000009:adverse effects* / Q000737:chemistry / Q000494:pharmacology; D020764:cdc42 GTP-Binding Protein / Q000037:antagonists & inhibitors / Q000378:metabolism*; D020830:rac1 GTP-Binding Protein / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000097767:Mitogen-Activated Protein Kinase Kinase Kinase 11
chemical_list: D004791:Enzyme Inhibitors; D018799:Intercellular Adhesion Molecule-1; D020930:MAP Kinase Kinase Kinases; D012333:RNA, Messenger; D015034:Zinc Oxide; D020764:cdc42 GTP-Binding Protein; D020830:rac1 GTP-Binding Protein; D000097767:Mitogen-Activated Protein Kinase Kinase Kinase 11; C107953:RAC1 protein, human