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Zhao-Jiang Du, Takuhiro Yamamoto, Tomoko Ueda, Mihoko Suzuki, Yasuo Tano, Motohiro Kamei; Activated Protein C Rescues the Retina from Ischemia-Induced Cell Death. Invest. Ophthalmol. Vis. Sci. 2011;52(2):987-993. doi: 10.1167/iovs.10-5557.
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Ischemia causes severe and persistent visual loss in many eye diseases, including central retinal vein occlusion (CRVO) and diabetic retinopathy. Activated protein C (APC) has been demonstrated to reduce the cell death associated with ischemia in the brain and kidney. This study was performed to examine the ability of APC to rescue hypoxia-induced retinal cell death in vitro and in vivo.
Retinal pigment epithelium (RPE) and photoreceptor cells were placed in either a normoxic or a hypoxic chamber. Immediately before they were subjected to ischemia, the cultures were treated with APC (3–240 μg/mL). Incubation was followed by an MTT assay to determine the number of viable cells. The activity of caspase-3, -8, and -9 in RPE cells was also analyzed. Various concentrations of APC were intravitreally injected in a rat CRVO model, followed by TUNEL staining to detect the in vivo effects of APC.
Lower concentrations of APC (0.3–30 μg/mL) showed a cell-protective effect against hypoxia in vitro, whereas higher concentrations (≥120 μg/mL) demonstrated cytotoxicity in both RPE and photoreceptor cells. Caspase-3, -8, and -9 were activated when the cells were exposed to hypoxia, but this activation was significantly inhibited by APC. Experimental CRVO-induced retinal cell apoptosis was reduced dramatically by intravitreal injection of APC.
APC can reduce ischemia-induced cytotoxicity both in vitro and in vivo via blocking the activation of caspase-3, -8, and -9. APC may be a promising candidate for protecting the retina from ischemia.
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