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N. Matsumura, M. Kamei, Z.-J. Du, P. Xie, T. Yamamoto, M. Suzuki, Y. Tano; Activated Protein C Rescues the Retinal Pigment Epithelial Cells From Ischemia-Induced Cell Death. Invest. Ophthalmol. Vis. Sci. 2009;50(13):2152.
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© ARVO (1962-2015); The Authors (2016-present)
Retinal ischemia causes severe and persistent visual loss in many eye diseases, such as central retinal vein occlusion (CRVO), retinopathy of prematurity (ROP), and diabetic retinopathy. Activated protein C (APC) has been demonstrated to reduce cell death associated with ischemia in the brain, the lung, and the kidney. The purpose of this study is to examine the ability of APC to rescue hypoxia-induced retinal cell death in vitro and to evaluate the protective effect of APC in a CRVO animal model.
Cultured human retinal pigment epithelial cells (ARPE-19) were placed either in a hypoxic or normoxic chamber. Immediately before placing in the ischemic condition, the cultures were treated with various concentrations of APC (ranging from 3 to 240 µg/ml). Incubation was followed by an MTT assay and TUNEL staining to determine the number of viable cells and apoptotic cells, respectively. Activity of caspases-3, -8, and -9 was also analyzed. To detect the in vivo effects of APC, various concentrations of APC were injected intravitreally in a rat CRVO model, followed by TUNEL staining.
Lower concentrations of APC (ranging from 3 to 60 µg/ml) showed a cell protective effect against hypoxic injury in vitro, while higher concentrations of APC (120 µg/ml or greater) demonstrated cytotoxicity. Caspases-3, -8, and -9 were activated when cells were subjected to hypoxia, but this activation was significantly inhibited by APC (P<0.01). Experimental CRVO-induced ischemia led to significant retinal cell apoptosis, which was reduced dramatically by intravitreal injection of APC at both lower (3 µg/ml) and higher (30 µg/ml) doses.
APC can reduce the cytotoxicity induced by ischemia both in vitro and in vivo via blocking the activation of caspases-3, -8, and -9. APC might be a promising candidate for protecting the retina from ischemic conditions and has potential as a therapeutic option for patients with CRVO, ROP, or diabetic retinopathy.
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