title: Long-term exposure to oxidized low-density lipoprotein enhances tumor necrosis factor-alpha-stimulated endothelial adhesiveness of monocytes by activating superoxide generation and redox-sensitive pathways.
abstract: This study was conducted to investigate the role of oxidized low-density lipoprotein (LDL) in monocyte/mononuclear cell (MNC) activation during atherogenesis. First, the activity of MNCs was studied in patients with coronary artery disease (CAD). Compared to normal subjects, phorbol 12-myristate 13-acetate (PMA)-stimulated reactive oxygen species (ROS) production and the adhesiveness to endothelial cells were increased in MNCs from CAD patients. After 24-h coculture with oxidized LDL, ROS elaboration of MNCs was significantly increased in CAD patients. It was further correlated to the endothelial adhesiveness of MNCs (r = 0.561, P < 0.05). Secondly, in an in vitro model for long-term, direct effects of oxidized LDL on murine monocytoid cells (MMCs), oxidized LDL, but not native LDL, induced ROS production of MMCs in a time-dependent manner up to a 4-day coincubation (261% elevation, P < 0.05). Four-day coincubation with ox-LDL enhanced cytoplasmic IkappaB phosphorylation and nuclear factor kappa B (NF-kappaB) translocation and increased endothelial adhesiveness of MMCs. The long-term exposure to oxidized LDL also significantly enhanced tumor necrosis factor-alpha (TNF-alpha)-stimulated ROS production and endothelial adhesiveness of MMCs, which could be completely abolished by the short-term existence of pyrrolidine dithiocarbamate (PDTC), an antioxidant and NF-kappaB blocker and by long-term coincubation with N-acetylcysteine, a nonspecific antioxidant. Accordingly, circulating MNCs were activated with increased endothelial adhesiveness in CAD patients. Long-term exposure to oxidized LDL could directly activate MNCs ex vivo and MMCs in vitro and enhance TNF-alpha-stimulated endothelial adhesiveness through the redox-dependent NF-kappaB transcriptional pathway. The findings suggest the pivotal role of oxidized LDL-induced oxidative stress in monocyte activation during atherogenesis.
authors.affiliation: National Yang-Ming University School of Medicine, Cardiovascular Research Center, Department of Medicine, Taipei Veterans General Hospital, Taiwan, Republic of China. jwchen@vghtpe.gov.tw
authors.forename: Jaw-Wen
authors.initials: JW
authors.lastname: Chen
authors.forename: Yung-Hsiang
authors.initials: YH
authors.lastname: Chen
authors.forename: Shing-Jong
authors.initials: SJ
authors.lastname: Lin
mesh_terms: D000111:Acetylcysteine / Q000494:pharmacology; D000818:Animals; D002448:Cell Adhesion; D002478:Cells, Cultured; D003324:Coronary Artery Disease / Q000276:immunology*; D004730:Endothelium, Vascular / Q000276:immunology*; D006801:Humans; D020672:I-kappa B Proteins / Q000378:metabolism; D008077:Lipoproteins, LDL / Q000494:pharmacology*; D051379:Mice; D009000:Monocytes / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000378:metabolism; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D013481:Superoxides / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
chemical_list: D020672:I-kappa B Proteins; D008077:Lipoproteins, LDL; D016328:NF-kappa B; C000606204:NFKBIA protein, human; C000606205:Nfkbia protein, mouse; D014409:Tumor Necrosis Factor-alpha; D013481:Superoxides; D000072000:NF-KappaB Inhibitor alpha; D000111:Acetylcysteine