title: Protective effects of 2,3-diaryl-substituted indole-based cyclooxygenase-2 inhibitors on oxidative modification of human low density lipoproteins in vitro.
abstract: It has been suggested that 2,3-diaryl-substituted indole-based cyclooxygenase-2 (COX-2) inhibitors (2,3-diaryl-indole coxibs) do not only appear as potent anti-inflammatory agents but also show the ability to scavenge reactive oxygen species (ROS). This led to the hypothesis that 2,3-diaryl-indole coxibs also may act as potent inhibitors of oxidative modification of low-density lipoprotein (LDL), which is considered a key factor in atherogenesis. The aim of this study was to explore i) the reactivity of a series of new synthesized 2,3-diaryl-indoles with several well characterized LDL oxidation systems and ii) subsequent effects on an inflammatory/atherogenic microenvironment. The results demonstrate that under the present experimental conditions 2,3-diaryl-indoles showed potent ROS scavenging activity and were able to markedly inhibit LDL oxidation. Subsequently, this led to a substantial decrease of modified LDL uptake by scavenger receptors in THP-1 macrophages in vitro and in rats in vivo. Moreover, modified LDL-mediated monocyte/neutrophil adhesion to endothelial cells, macrophage NFκB activation, as well as macrophage and endothelial cell cytokine release was diminished in vitro. The reduction of modified LDL-induced atherogenic effects by antioxidant 2,3-diaryl-indole coxibs may widen the therapeutic window of COX-2 targeted treatment.
authors.affiliation: Helmholtz-Zentrum Dresden-Rossendorf, Institute of Radiopharmaceutical Cancer Research, Department Radiopharmaceutical and Chemical Biology, Dresden, Germany.|Technische Universität Dresden, Department of Chemistry and Food Chemistry, Dresden, Germany.
authors.forename: Jens
authors.initials: J
authors.lastname: Pietzsch
authors.affiliation: Helmholtz-Zentrum Dresden-Rossendorf, Institute of Radiopharmaceutical Cancer Research, Department Radiopharmaceutical and Chemical Biology, Dresden, Germany.|Technische Universität Dresden, Department of Chemistry and Food Chemistry, Dresden, Germany.
authors.forename: Markus
authors.initials: M
authors.lastname: Laube
authors.affiliation: Helmholtz-Zentrum Dresden-Rossendorf, Institute of Radiopharmaceutical Cancer Research, Department Radiopharmaceutical and Chemical Biology, Dresden, Germany.|Technische Universität Dresden, Department of Chemistry and Food Chemistry, Dresden, Germany.
authors.forename: Nicole
authors.initials: N
authors.lastname: Bechmann
authors.affiliation: Helmholtz-Zentrum Dresden-Rossendorf, Institute of Radiopharmaceutical Cancer Research, Department Radiopharmaceutical and Chemical Biology, Dresden, Germany.|Technische Universität Dresden, Medical Faculty and University Hospital, Centre for Translational Bone, Joint, and Soft Tissue Research, Dresden, Germany.
authors.forename: Franz-Jacob
authors.initials: FJ
authors.lastname: Pietzsch
authors.affiliation: Helmholtz-Zentrum Dresden-Rossendorf, Institute of Radiopharmaceutical Cancer Research, Department Radiopharmaceutical and Chemical Biology, Dresden, Germany.
authors.forename: Torsten
authors.initials: T
authors.lastname: Kniess
mesh_terms: D000818:Animals; D000975:Antioxidants; D052246:Cyclooxygenase 2 Inhibitors / Q000627:therapeutic use*; D006801:Humans; D008077:Lipoproteins, LDL / Q000032:analysis / Q000378:metabolism*; D008297:Male; D010084:Oxidation-Reduction; D051381:Rats; D011920:Rats, Inbred WF; D017382:Reactive Oxygen Species
chemical_list: D000975:Antioxidants; D052246:Cyclooxygenase 2 Inhibitors; D008077:Lipoproteins, LDL; D017382:Reactive Oxygen Species; C099252:oxidized low density lipoprotein
keywords: Antioxidants; atherogenesis; inflammation; lipid peroxidation; protein oxidation; radical scavenger; reactive oxygen species (ROS); selective cyclooxygenase-2 (COX-2) inhibitors (coxibs)