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

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概要

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• Thiazolidinediones, peroxisome proliferators-activated receptor gamma (PPARγ) 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 PPARγ 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 μM) 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 μM) and bisphenol A diglycidyl ether (10 μM). 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 μM). 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 μM) and ERK inhibitor PD98056 (10 μM). 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.

• 社団法人 日本薬理学会の論文
• 2009-09-20

著者

• Thapa Dinesh

  College Of Pharmacy Yeungnam University

• Park Byung

  College Of Pharmacy Yeungnam University

• LEE JONG

  College of Veterinary Medicine, Chonnam National University

• KIM Jung-Ae

  College of Pharmacy, Yeungnam University

• Kim Jung-ae

  College Of Pharmacy Yeungnam University

• PARK Su-Young

  College of Pharmacy, Yeungnam University

• Park Su-young

  College Of Pharmacy Yeungnam University

• Lee Jong

  College Of Pharmacy Yeungnam University

• Lee Jong

  College Of Forest And Environmental Sciences Kangwon National University

• PARK Byung

  College of Pharmacy, Yeungnam University

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