Light-induced photoreceptor apoptosis in vivo requires neuronal nitric-oxide synthase and guanylate cyclase activity and is caspase-3 independent
Light-induced photoreceptor apoptosis in vivo requires neuronal nitric-oxide synthase and guanylate cyclase activity and is caspase-3 independent
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DOI：
10.1074/jbc.m005359200
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发表时间：
2001-06-22
影响因子：
4.8
通讯作者：
Cotter, TG
中科院分区：
文献类型：
--
作者：
Donovan, M;Carmody, RJ;Cotter, TG
细胞凋亡是遗传性和诱导性视网膜变性中感光细胞死亡的方式。然而，在视网膜营养不良的人类病例和动物模型中感光细胞死亡的分子机制仍然不明确。Balb/c小鼠暴露于过量的白色光导致感光细胞凋亡。本研究描述了Balb/c小鼠暴露于白色光诱导视网膜变性期间和之后发生的分子事件。我们证明了早期增加细胞内钙离子水平感光细胞凋亡过程中，伴随着显着的超氧化物生成和线粒体膜去极化的事件，此外，我们表明，抑制神经元一氧化氮合酶（nNOS）的7-硝基吲唑是足以防止视网膜变性牵连神经元一氧化氮（NO）在这个模型中的关键作用。我们证明，鸟苷酸环化酶，一氧化氮的下游效应的抑制，也可以防止感光细胞凋亡，证明鸟苷酸环化酶在这个模型中也起着至关重要的作用。最后，我们的研究结果表明，半胱天冬酶3，经常被认为是细胞凋亡的关键执行者之一，在视网膜变性过程中不被激活。总之，本文提供的数据表明，光诱导的光感受器细胞凋亡在体内介导的激活nNOS和鸟苷酸环化酶，是半胱天冬酶-3-独立。
Apoptosis is the mode of photoreceptor cell death in inherited and induced retinal degeneration. However, the molecular mechanisms of photoreceptor cell death in human cases and animal models of retinal dystrophies remain undefined. Exposure of Balb/c mice to excessive levels of white Light results in photoreceptor apoptosis, This study delineates the molecular events occurring during and subsequent to the induction of retinal degeneration by exposure to white light in Balb/c mice. We demonstrate an early increase in intracellular calcium levels during photoreceptor apoptosis, an event that is accompanied by significant superoxide generation and mitochondrial membrane depolarization, Furthermore, we show that inhibition of neuronal nitric-oxide synthase (nNOS) by 7-nitroindazole is sufficient to prevent retinal degeneration implicating a key role for neuronal nitric oxide (NO) in this model. We demonstrate that inhibition of guanylate cyclase, a downstream effector of NO, also prevents photoreceptor apoptosis demonstrating that guanylate cyclase too plays an essential role in this model. Finally, our results demonstrate that caspase 3, frequently considered to be one of the key executioners of apoptosis, is not activated during retinal degeneration. In summary, the data presented here demonstrate that light-induced photoreceptor apoptosis in vivo is mediated by the activation of nNOS and guanylate cyclase and is caspase-3-independent.