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

Abstract. 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 VEGFinduced angiogenesis were mediated through the suppression of VEGF-induced ROS production and ERK phosphorylation.

Rosiglitazone, a PPAR-γ agonist, inhibits VEGF secretion by peripheral blood mononuclear cells and ROS production by human leukocytes

“…Park et al [3] reported that the effects of troglitazone on VEGF-induced MMP-2 expression are comparable with those observed for diphenyleneiodonium (DPI), suggesting that the inhibition of NADPH-oxidase is mediated by PPAR-c. Similar results were obtained by Kim et al [15] and Guo et al [16] following studies of the effects of PPAR-c agonists on phorbol ester-treated glioma and osteoblast cells.…”

“…Derivatives of thiazolidinediones (also known as glitazones) act as efficient exogenous ligands for PPAR-c [1,2], and a number have been shown to possess antidiabetic, anti-inflammatory or anti-angiogenic activities. Troglitazone, for example, inhibits vascular endothelial growth factor (VEGF)-induced angiogenic signaling through the suppression of reactive oxygen species (ROS) and the production of matrix metalloprotease-2 (MMP-2) [3], while rosiglitazone inhibits angiogenesis in tumor proliferating cells [4].…”

Identification of troglitazone responsive genes: induction of RTP801 during troglitazone-induced apoptosis in Hep 3B cells

“…On the other hand, genes related with angiogenesis, such as VEGF-C, were downregulated upon troglitazone treatment, suggesting that troglitazone inhibits angiogenesis by reducing VEGF-C production. A recent report also suggested a regulatory role for troglitazone in VEGFinduced angiogenic signaling (9). Genes implicated in apoptosis and cell cycle regulation are HIF-1 responsive RTP801, DOC1 and SNK.…”

Peroxisome Proliferator-Activated Receptor-γ (PPAR-γ) Activation Confers Functional Neuroprotection in Global Ischemia

“…Cerebral neuroprotection produced by PPARc agonists could be due to any of several mechanisms including oxidative stress modulation (Collino et al 2006), anti-inflammatory effects (Collino et al 2006;Sundararajan et al 2005), induction of mitochondrial biogenesis (Strum et al 2007) and/or through neuronal up-regulation of Bcl-2 (Fuenzalida et al 2007). In addition, several recent studies have shown that PPARc agonists reduce damage in cerebral ischemia by inhibition of matrix metalloproteinase-9 Wang et al 2009) or by enhancement of angiogenesis (Chu et al 2006), although the effects of PPARc agonists on angiogenesis in general are unclear and may vary between models and dosing regimes since both promotion (Biscetti et al 2008(Biscetti et al , 2009aTian et al 2009) and inhibition (Aljada et al 2008;Park et al 2009;Scoditti et al 2010) of angiogenesis have been reported following PPARc agonist administration.…”