Yamamoto M, Sato N, Tajima H, Furuke K, Ohira A, Honda Y, Yodoi J
Department of Ophthalmology, Faculty of Medicine, Kyoto University, Kyoto, Japan.
Exp Eye Res. 1997 Nov;65(5):645-52. doi: 10.1006/exer.1997.0370.
Human thioredoxin is one of the oxidative stress-inducible proteins and has a protective function against oxidant-induced injury. To evaluate the possible involvement of thioredoxin in the cytoprotective function of prostaglandin E1, we analysed the effect of prostaglandin E1 on cellular injury by hydrogen peroxide and intracellular thioredoxin induction. Cellular survival of human retinal pigment epithelial cell line, established from normal retinal pigment epithelial cells, following exposure to hydrogen peroxide was markedly improved by pretreatment of 1 microm prostaglandin E1. Thioredoxin expression was augmented in a dose-dependent manner when retinal pigment epithelial cells were pretreated with 10 nm-1 microm prostaglandin E1 1 hr before the exposure to hydrogen peroxide. Intracellular cyclic AMP level was elevated by Prostaglandin E1 when the cells were simultaneously exposed to hydrogen peroxide. Forskolin, an activator of adenylate cyclase, and dibutylyl cAMP, a cyclic AMP analog, could also induce thioredoxin and extend survival of retinal pigment epithelial cells. On the other hand, thioredoxin induction and cellular protection by prostaglandin E1 was blocked by Rp diastereoisomer of cyclic adenosine 3', 5', monophosphorothioate, a competitive inhibitor of cyclic AMP dependent protein kinase. Thioredoxin induction was augmented significantly by pretreatment with prostaglandin I2, a stimulator of cyclic AMP dependent signal pathway, while treatment with prostaglandin F2alpha, a stimulator of inositol phosphate-dependent signal pathway, failed to enhance thioredoxin. These findings indicate that prostaglandin E1 has a cytoprotective activity against oxidative injury, partly through thioredoxin induction via cyclic AMP dependent pathway.
人硫氧还蛋白是氧化应激诱导蛋白之一，对氧化剂诱导的损伤具有保护作用。为了评估硫氧还蛋白可能参与前列腺素E1的细胞保护功能，我们分析了前列腺素E1对过氧化氢诱导的细胞损伤和细胞内硫氧还蛋白诱导的影响。用1微摩尔前列腺素E1预处理后，由正常视网膜色素上皮细胞建立的人视网膜色素上皮细胞系在暴露于过氧化氢后的细胞存活率显著提高。当视网膜色素上皮细胞在暴露于过氧化氢前1小时用10纳米至1微摩尔前列腺素E1预处理时，硫氧还蛋白表达呈剂量依赖性增加。当细胞同时暴露于过氧化氢时，前列腺素E1可提高细胞内环磷酸腺苷水平。腺苷酸环化酶激活剂福斯高林和环磷酸腺苷类似物二丁酰环磷腺苷也可诱导硫氧还蛋白并延长视网膜色素上皮细胞的存活时间。另一方面，环磷腺苷3',5'-单磷酸硫代磷酸酯的Rp非对映异构体（一种环磷酸腺苷依赖性蛋白激酶的竞争性抑制剂）可阻断前列腺素E1诱导的硫氧还蛋白和细胞保护作用。环磷酸腺苷依赖性信号通路刺激剂前列腺素I2预处理可显著增强硫氧还蛋白的诱导作用，而肌醇磷酸依赖性信号通路刺激剂前列腺素F2α处理则未能增强硫氧还蛋白的表达。这些发现表明，前列腺素E1对氧化损伤具有细胞保护活性，部分是通过环磷酸腺苷依赖性途径诱导硫氧还蛋白实现的。
