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Peroxisome proliferator-activated receptor-gamma ligands inhibit choroidal neovascularization
Purpose:
To determine the antiangiogenic effects of peroxisome proliferator-activated receptor (PPAR)-gamma 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-gamma 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-gamma ligands, troglitazone (TRO) and rosiglitazone (RSG; 0.1-20 microM), 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 burns per eye) and cynomolgus monkey eyes (two experimental, two control, seven paramacular burns per eye) was assessed by fluorescein angiography and histologic evaluation. RESULTS. PPAR-gamma1 was expressed in both RPE and CEC. PPAR-gamma 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-gamma ligands suggests the potential application of these agents in the large group of patients with age-related macular degeneration complicated by CNV.
Insights
Peroxisome proliferator-activated receptor (PPAR)-gamma agonists demonstrated significant antiangiogenic effects, inhibiting choroidal neovascularization (CNV) in both cell cultures and animal models. This suggests potential therapeutic applications for age-related macular degeneration.
Area of Science:
- Ophthalmology
- Molecular Biology
- Pharmacology
Background:
- Choroidal neovascularization (CNV) is a key factor in age-related macular degeneration (AMD).
- Peroxisome proliferator-activated receptor (PPAR)-gamma is implicated in cellular processes relevant to angiogenesis.
Purpose of the Study:
- To investigate the antiangiogenic effects of PPAR-gamma agonists on ocular cells.
- To evaluate the efficacy of PPAR-gamma agonists in an in vivo model of laser-induced CNV.
Main Methods:
- PPAR-gamma expression was analyzed in retinal pigment epithelial (RPE) cells and choroidal endothelial cells (CECs).
- The impact of PPAR-gamma ligands (troglitazone and rosiglitazone) on cell proliferation, migration, and tube formation was assessed in vitro.
- The effect of troglitazone on laser-induced CNV in rat and cynomolgus monkey eyes was evaluated using angiography and histology.
Main Results:
- PPAR-gamma1 was expressed in RPE and CECs.
- PPAR-gamma ligands significantly inhibited VEGF-induced RPE and CEC proliferation and migration, as well as CEC tube formation.
- Intravitreous injection of troglitazone markedly inhibited CNV in rats and showed similar effects in monkey eyes, with no apparent adverse effects.
Conclusions:
- PPAR-gamma ligands inhibit choroidal angiogenesis in vitro and CNV in vivo.
- These findings suggest that PPAR-gamma agonists hold potential for treating CNV in patients with AMD.