title: Troglitazone inhibits vascular endothelial growth factor-induced angiogenic signaling via suppression of reactive oxygen species production and extracellular signal-regulated kinase phosphorylation in endothelial cells.
abstract: Thiazolidinediones, peroxisome proliferators-activated receptor gamma (PPARgamma) ligands, have been recognized as a potential therapeutic agents for the treatment of pathological neovascularization. In the present study, we examined the molecular mechanism by which troglitazone (TROG), a PPARgamma agonist, exerts its inhibitory action in vascular endothelial growth factor (VEGF)-induced angiogenesis signaling. In an in vitro angiogenesis model using human umbilical vein endothelial cells, TROG (20 muM) significantly suppressed VEGF-induced cell proliferation and invasion of the cells into the Matrigel basement membrane, which was not reversed by treatment with PPAR antagonists, GW9662 (10 muM) and bisphenol A diglycidyl ether (10 muM). TROG also blocked VEGF-induced reactive oxygen species (ROS) production and its downstream extracellular signal-regulated kinase (ERK) phosphorylation, and this inhibitory effect was not reversed by GW9662 (10 muM). The antiangiogenic activity of TROG correlated with suppression of VEGF-induced matrix metalloproteinase (MMP)-2 and membrane type 1 (MT1)-MMP expression. In addition, the effects of TROG on VEGF-induced MMP-2 and MT1-MMP expression were comparable to those of the NADPH oxidase inhibitor diphenylene iodium (10 muM) and ERK inhibitor PD98056 (10 muM). Furthermore, in an in vivo angiogenesis system using a chick chorioallantoic membrane model, TROG dose-dependently inhibited VEGF-induced angiogenesis, which was similar to the inhibitory effect of N-acetylcysteine on VEGF-induced angiogenesis. The results suggest that the inhibitory effects of TROG on VEGF-induced angiogenesis were mediated through the suppression of VEGF-induced ROS production and ERK phosphorylation.
authors.affiliation: College of Pharmacy, Yeungnam University, Korea.
authors.forename: Byung Chul
authors.initials: BC
authors.lastname: Park
authors.forename: Dinesh
authors.initials: D
authors.lastname: Thapa
authors.forename: Jong Suk
authors.initials: JS
authors.lastname: Lee
authors.forename: Su-Young
authors.initials: SY
authors.lastname: Park
authors.forename: Jung-Ae
authors.initials: JA
authors.lastname: Kim
mesh_terms: D020533:Angiogenesis Inhibitors / Q000494:pharmacology; D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D002642:Chick Embryo; D002839:Chromans / Q000494:pharmacology*; D042783:Endothelial Cells / Q000187:drug effects* / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D005260:Female; D006801:Humans; D020781:Matrix Metalloproteinase 1 / Q000187:drug effects; D020778:Matrix Metalloproteinase 2 / Q000187:drug effects; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D010766:Phosphorylation / Q000187:drug effects; D017382:Reactive Oxygen Species / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D045162:Thiazolidinediones / Q000494:pharmacology*; D000077288:Troglitazone; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors* / Q000494:pharmacology
chemical_list: D020533:Angiogenesis Inhibitors; D002839:Chromans; D017382:Reactive Oxygen Species; D045162:Thiazolidinediones; D042461:Vascular Endothelial Growth Factor A; D048049:Extracellular Signal-Regulated MAP Kinases; D020778:Matrix Metalloproteinase 2; D020781:Matrix Metalloproteinase 1; D000077288:Troglitazone