Peroxisome proliferator-activated receptor-γ ligands inhibit choroidal neovascularization

Toshinori Murata, Shikun He, Masanori Hangai, Tatsuro Ishibashi, Xiao Ping Xi, Sarah Kim, Willa A. Hsueh, Stephen J. Ryan, Ronald E. Law, David R. Hinton

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Abstract

PURPOSE. To determine the antiangiogenic effects of peroxisome proliferator-activated receptor (PPAR)-γ-agonists on ocular cells involved in the pathogenesis of choroidal neovascularization (CNV) in vitro and on experimental laser photocoagulation-induced CNV in vivo. METHODS. PPAR-γ expression in human retinal pigment epithelial (RPE) cells and bovine choroidal endothelial cells (CECs) was determined using an RNase protection assay and Western blot analysis. Two PPAR-γ ligands, troglitazone (TRO) and rosiglitazone (RSG; 0.1-20 μM), were used to assess effects on RPE and CEC proliferation and migration and CEC tube formation in response to vascular endothelial growth factor (VEGF). The effects of intravitreal injection of TRO on laser photocoagulation-induced CNV lesions in rat eyes (15 experimental, 15 control, nine bums per eye) and cynomolgus monkey eyes (two experimental, two control, seven paramacular bums per eye) was assessed by fluorescein angiography and histologic evaluation. RESULTS. PPAR-γ1 was expressed in both RPE and CEC. PPAR-γ ligands significantly inhibited VEGF- induced migration and proliferation in both cell types and tube formation of CEC in a dose-response manner. CNV in rats was markedly inhibited by intravitreous injection of TRO (P < 0.001). Lesions showed significantly less fluorescein leakage and were histologically thinner in the TRO-treated animals. Similar findings were present in the TRO-treated lesions in two monkey eyes. The drug showed no apparent adverse effects in the adjacent retina or in control eyes. CONCLUSIONS. The inhibition of VEGF-induced choroidal angiogenesis in vitro, and CNV in vivo by PPAR-γ ligands suggests the potential application of these agents in the large group of patients with age-related macular degeneration complicated by CNV.

Original languageEnglish
Pages (from-to)2309-2317
Number of pages9
JournalInvestigative Ophthalmology and Visual Science
Volume41
Issue number8
Publication statusPublished - Jul 24 2000

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troglitazone
Choroidal Neovascularization
Peroxisome Proliferator-Activated Receptors
Ligands
Endothelial Cells
Retinal Pigments
Vascular Endothelial Growth Factor A
rosiglitazone
Light Coagulation
Lasers
Intravitreal Injections
Macaca fascicularis
Fluorescein Angiography
Macular Degeneration
Ribonucleases
Fluorescein
Cell Movement
Haplorhini
Retina
Western Blotting

All Science Journal Classification (ASJC) codes

  • Ophthalmology
  • Sensory Systems
  • Cellular and Molecular Neuroscience

Cite this

Peroxisome proliferator-activated receptor-γ ligands inhibit choroidal neovascularization. / Murata, Toshinori; He, Shikun; Hangai, Masanori; Ishibashi, Tatsuro; Xi, Xiao Ping; Kim, Sarah; Hsueh, Willa A.; Ryan, Stephen J.; Law, Ronald E.; Hinton, David R.

In: Investigative Ophthalmology and Visual Science, Vol. 41, No. 8, 24.07.2000, p. 2309-2317.

Research output: Contribution to journalArticle

Murata, T, He, S, Hangai, M, Ishibashi, T, Xi, XP, Kim, S, Hsueh, WA, Ryan, SJ, Law, RE & Hinton, DR 2000, 'Peroxisome proliferator-activated receptor-γ ligands inhibit choroidal neovascularization', Investigative Ophthalmology and Visual Science, vol. 41, no. 8, pp. 2309-2317.
Murata, Toshinori ; He, Shikun ; Hangai, Masanori ; Ishibashi, Tatsuro ; Xi, Xiao Ping ; Kim, Sarah ; Hsueh, Willa A. ; Ryan, Stephen J. ; Law, Ronald E. ; Hinton, David R. / Peroxisome proliferator-activated receptor-γ ligands inhibit choroidal neovascularization. In: Investigative Ophthalmology and Visual Science. 2000 ; Vol. 41, No. 8. pp. 2309-2317.
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abstract = "PURPOSE. To determine the antiangiogenic effects of peroxisome proliferator-activated receptor (PPAR)-γ-agonists on ocular cells involved in the pathogenesis of choroidal neovascularization (CNV) in vitro and on experimental laser photocoagulation-induced CNV in vivo. METHODS. PPAR-γ expression in human retinal pigment epithelial (RPE) cells and bovine choroidal endothelial cells (CECs) was determined using an RNase protection assay and Western blot analysis. Two PPAR-γ ligands, troglitazone (TRO) and rosiglitazone (RSG; 0.1-20 μM), were used to assess effects on RPE and CEC proliferation and migration and CEC tube formation in response to vascular endothelial growth factor (VEGF). The effects of intravitreal injection of TRO on laser photocoagulation-induced CNV lesions in rat eyes (15 experimental, 15 control, nine bums per eye) and cynomolgus monkey eyes (two experimental, two control, seven paramacular bums per eye) was assessed by fluorescein angiography and histologic evaluation. RESULTS. PPAR-γ1 was expressed in both RPE and CEC. PPAR-γ ligands significantly inhibited VEGF- induced migration and proliferation in both cell types and tube formation of CEC in a dose-response manner. CNV in rats was markedly inhibited by intravitreous injection of TRO (P < 0.001). Lesions showed significantly less fluorescein leakage and were histologically thinner in the TRO-treated animals. Similar findings were present in the TRO-treated lesions in two monkey eyes. The drug showed no apparent adverse effects in the adjacent retina or in control eyes. CONCLUSIONS. The inhibition of VEGF-induced choroidal angiogenesis in vitro, and CNV in vivo by PPAR-γ ligands suggests the potential application of these agents in the large group of patients with age-related macular degeneration complicated by CNV.",
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T1 - Peroxisome proliferator-activated receptor-γ ligands inhibit choroidal neovascularization

AU - Murata, Toshinori

AU - He, Shikun

AU - Hangai, Masanori

AU - Ishibashi, Tatsuro

AU - Xi, Xiao Ping

AU - Kim, Sarah

AU - Hsueh, Willa A.

AU - Ryan, Stephen J.

AU - Law, Ronald E.

AU - Hinton, David R.

PY - 2000/7/24

Y1 - 2000/7/24

N2 - PURPOSE. To determine the antiangiogenic effects of peroxisome proliferator-activated receptor (PPAR)-γ-agonists on ocular cells involved in the pathogenesis of choroidal neovascularization (CNV) in vitro and on experimental laser photocoagulation-induced CNV in vivo. METHODS. PPAR-γ expression in human retinal pigment epithelial (RPE) cells and bovine choroidal endothelial cells (CECs) was determined using an RNase protection assay and Western blot analysis. Two PPAR-γ ligands, troglitazone (TRO) and rosiglitazone (RSG; 0.1-20 μM), were used to assess effects on RPE and CEC proliferation and migration and CEC tube formation in response to vascular endothelial growth factor (VEGF). The effects of intravitreal injection of TRO on laser photocoagulation-induced CNV lesions in rat eyes (15 experimental, 15 control, nine bums per eye) and cynomolgus monkey eyes (two experimental, two control, seven paramacular bums per eye) was assessed by fluorescein angiography and histologic evaluation. RESULTS. PPAR-γ1 was expressed in both RPE and CEC. PPAR-γ ligands significantly inhibited VEGF- induced migration and proliferation in both cell types and tube formation of CEC in a dose-response manner. CNV in rats was markedly inhibited by intravitreous injection of TRO (P < 0.001). Lesions showed significantly less fluorescein leakage and were histologically thinner in the TRO-treated animals. Similar findings were present in the TRO-treated lesions in two monkey eyes. The drug showed no apparent adverse effects in the adjacent retina or in control eyes. CONCLUSIONS. The inhibition of VEGF-induced choroidal angiogenesis in vitro, and CNV in vivo by PPAR-γ ligands suggests the potential application of these agents in the large group of patients with age-related macular degeneration complicated by CNV.

AB - PURPOSE. To determine the antiangiogenic effects of peroxisome proliferator-activated receptor (PPAR)-γ-agonists on ocular cells involved in the pathogenesis of choroidal neovascularization (CNV) in vitro and on experimental laser photocoagulation-induced CNV in vivo. METHODS. PPAR-γ expression in human retinal pigment epithelial (RPE) cells and bovine choroidal endothelial cells (CECs) was determined using an RNase protection assay and Western blot analysis. Two PPAR-γ ligands, troglitazone (TRO) and rosiglitazone (RSG; 0.1-20 μM), were used to assess effects on RPE and CEC proliferation and migration and CEC tube formation in response to vascular endothelial growth factor (VEGF). The effects of intravitreal injection of TRO on laser photocoagulation-induced CNV lesions in rat eyes (15 experimental, 15 control, nine bums per eye) and cynomolgus monkey eyes (two experimental, two control, seven paramacular bums per eye) was assessed by fluorescein angiography and histologic evaluation. RESULTS. PPAR-γ1 was expressed in both RPE and CEC. PPAR-γ ligands significantly inhibited VEGF- induced migration and proliferation in both cell types and tube formation of CEC in a dose-response manner. CNV in rats was markedly inhibited by intravitreous injection of TRO (P < 0.001). Lesions showed significantly less fluorescein leakage and were histologically thinner in the TRO-treated animals. Similar findings were present in the TRO-treated lesions in two monkey eyes. The drug showed no apparent adverse effects in the adjacent retina or in control eyes. CONCLUSIONS. The inhibition of VEGF-induced choroidal angiogenesis in vitro, and CNV in vivo by PPAR-γ ligands suggests the potential application of these agents in the large group of patients with age-related macular degeneration complicated by CNV.

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