title: Enhanced plasminogen activator inhibitor-1 expression in transgenic mice with hepatocyte-specific overexpression of superoxide dismutase or glutathione peroxidase.
abstract: In this study, we developed a double-transgenic mouse model allowing hepatocyte-specific and regulated expression of the redox-modifying enzymes copper/zinc superoxide dismutase (SOD) and glutathione peroxidase (GPX) by using a tetracycline-regulatable gene expression system. Within this system, the SOD and GPX level can be regulated deliberately by addition or removal of doxycycline hydrochloride to the drinking water. As reactive oxygen species (ROS) have been implicated in a number of pathological conditions, such as atherosclerosis, thrombosis, or liver fibrosis, processes that are also frequently associated with enhanced levels of plasminogen activator inhibitor-1 (PAI-1), it was the aim of the present study to investigate the influence of SOD and GPX overexpression on the regulation of PAI-1. PAI-1 mRNA and protein levels in tetracycline transactivator-dependent SOD-overexpressing double-transgenic mice reached values 2.5- to threefold above the normal mRNA level. By applying doxycycline, a deinduction of the PAI-1 levels was observed. By using the same protocol, PAI-1 mRNA and protein levels were enhanced in GPX double-transgenic mice, and again this response was blunted by the addition of doxycycline. These studies provide some new information regarding the role of ROS within the proteolytic processes in hepatocytes that require PAI-1.
authors.affiliation: IBA GmbH, Rudolf-Wissell-Str. 28, 37079 Göttingen, Germany.
authors.forename: Kai
authors.initials: K
authors.lastname: Franke
authors.forename: Katja
authors.initials: K
authors.lastname: Curth
authors.forename: Jacek
authors.initials: J
authors.lastname: Lenart
authors.forename: Doreen
authors.initials: D
authors.lastname: Knochenhauer
authors.forename: Thomas
authors.initials: T
authors.lastname: Kietzmann
mesh_terms: D000818:Animals; D005355:Fibrosis; D005786:Gene Expression Regulation; D005979:Glutathione Peroxidase / Q000235:genetics / Q000378:metabolism*; D022781:Hepatocytes / Q000166:cytology / Q000473:pathology / Q000502:physiology*; D051379:Mice; D008822:Mice, Transgenic; D017395:Plasminogen Activator Inhibitor 1 / Q000235:genetics / Q000378:metabolism*; D011500:Protein Synthesis Inhibitors / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D013482:Superoxide Dismutase / Q000235:genetics / Q000378:metabolism*; D013752:Tetracycline / Q000378:metabolism
chemical_list: D017395:Plasminogen Activator Inhibitor 1; D011500:Protein Synthesis Inhibitors; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; D005979:Glutathione Peroxidase; D013482:Superoxide Dismutase; D013752:Tetracycline