Protective effects of 2,3-diaryl-substituted indole-based cyclooxygenase-2 inhibitors on oxidative modification of human low density lipoproteins in vitro

Article type: Research Article

Authors: Pietzsch, Jens^{a; b; *} | Laube, Markus^{a; b} | Bechmann, Nicole^{a; b} | Pietzsch, Franz-Jacob^{a; c} | Kniess, Torsten^a

Affiliations: [a] Helmholtz-Zentrum Dresden-Rossendorf, Institute of Radiopharmaceutical Cancer Research, Department Radiopharmaceutical and Chemical Biology, Dresden, Germany | [b] Technische Universität Dresden, Department of Chemistry and Food Chemistry, Dresden, Germany | [c] Technische Universität Dresden, Medical Faculty and University Hospital, Centre for Translational Bone, Joint, and Soft Tissue Research, Dresden, Germany

Correspondence: [*] Corresponding author: Jens Pietzsch. Tel.: +49 3512602622; Fax: +49 35126012622; j.pietzsch@hzdr.de

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 conditions2,3-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.

Keywords: Antioxidants, atherogenesis, selective cyclooxygenase-2 (COX-2) inhibitors (coxibs), inflammation, lipid peroxidation, protein oxidation, radical scavenger, reactive oxygen species (ROS)

DOI: 10.3233/CH-141923

Journal: Clinical Hemorheology and Microcirculation, vol. 61, no. 4, pp. 615-632, 2015