title: Exposure to High-Dose Diesel Exhaust Particles Induces Intracellular Oxidative Stress and Causes Endothelial Apoptosis in Cultured In Vitro Capillary Tube Cells.
abstract: Previous studies suggest a direct correlation between exposure to diesel exhaust particles (DEP) and the onset of vascular permeability, presumably through the disruption of the adherens junctions. This would lead to deleterious effects on vasculature, such as acute myocardial infarction and atherosclerosis. Although the mechanism remains unclear, we demonstrate DEP-induced mitochondrial reactive oxygen species generation, which may be a central cause of the above vascular disorders. In vitro capillary-like HUVEC tube cells are used in this study and show that acute DEP exposure stimulates ATP depletion, followed by depolarization of their actin cytoskeleton, which sequentially inhibits PI3K/Akt activity and induces endothelial apoptosis. These events are accompanied by induction of p53/Mdm2 feedback regulation at 10 µg/mL DEP and produce 20 % cell apoptosis. Nevertheless, 100 µg/mL DEP augments tube cell apoptosis up to 70 % but disrupts the p53 negative regulator Mdm2. Addition of N-acetylcysteine provides substantial protection against the cytotoxic effects of DEP. In summary, exposure to a low dose of DEP actin triggers cytoskeleton depolarization, reduces PI3K/Akt activity, and induces a p53/Mdm2 feedback loop, and a high dose causes apoptosis by depleting Mdm2.
authors.affiliation: Department of Biomedical Engineering, College of Engineering, Chung Yuan Christian University, 200 Chung Pei Road, Chungli City, 32023, Taoyuan, Taiwan.
authors.forename: Chia-Yi
authors.initials: CY
authors.lastname: Tseng
authors.affiliation: Department of Bioscience Technology, College of Science, Chung Yuan Christian University, 200 Chung Pei Road, Chungli City, 32023, Taoyuan, Taiwan.
authors.forename: Jhih-Syuan
authors.initials: JS
authors.lastname: Wang
authors.affiliation: Department of Bioscience Technology, College of Science, Chung Yuan Christian University, 200 Chung Pei Road, Chungli City, 32023, Taoyuan, Taiwan.
authors.forename: Yu-Jung
authors.initials: YJ
authors.lastname: Chang
authors.affiliation: Department of Bioscience Technology, College of Science, Chung Yuan Christian University, 200 Chung Pei Road, Chungli City, 32023, Taoyuan, Taiwan.
authors.forename: Jing-Fen
authors.initials: JF
authors.lastname: Chang
authors.affiliation: Department of Bioscience Technology, College of Science, Chung Yuan Christian University, 200 Chung Pei Road, Chungli City, 32023, Taoyuan, Taiwan. chao@cycu.edu.tw.
authors.forename: Ming-Wei
authors.initials: MW
authors.lastname: Chao
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000975:Antioxidants / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D002196:Capillaries / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004734:Energy Metabolism / Q000187:drug effects; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D018384:Oxidative Stress / Q000187:drug effects*; D052638:Particulate Matter / Q000633:toxicity*; D058539:Phosphatidylinositol 3-Kinase / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051736:Proto-Oncogene Proteins c-mdm2 / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013481:Superoxides / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D001335:Vehicle Emissions / Q000633:toxicity*
chemical_list: D000975:Antioxidants; D052638:Particulate Matter; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D001335:Vehicle Emissions; D013481:Superoxides; D000255:Adenosine Triphosphate; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2; D058539:Phosphatidylinositol 3-Kinase; D051057:Proto-Oncogene Proteins c-akt
keywords: Apoptosis; Diesel exhaust particles (DEP); Human umbilical vein endothelial cell (HUVEC); Mouse double minute 2 (Mdm2); N-acetylcysteine (NAC); Phosphoinositide 3-kinase (PI3K); Protein kinase B (Akt); Reactive oxygen species (ROS)