Involvement of All-trans-retinal in Acute Light-induced Retinopathy of Mice
Involvement of All-trans-retinal in Acute Light-induced Retinopathy of Mice
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DOI：
10.1074/jbc.m900322200
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发表时间：
2009-05-29
影响因子：
4.8
通讯作者：
Palczewski, Krzysztof
中科院分区：
文献类型：
--
作者：
Maeda, Akiko;Maeda, Tadao;Palczewski, Krzysztof
暴露在强光下会导致人类和实验动物的视觉功能障碍和视网膜感光器损伤，但其机制仍不清楚。我们研究了类维生素A循环（即分别通过连续生成11-顺式视黄醛和清除全反式视黄醛来实现视力所需的一系列生化反应）是否可能参与其中。此前，我们报道，缺乏两种负责清除全反式视网膜的酶的小鼠，即光感受器特异性ABCA4（ATP结合盒转运蛋白4）和RDH8（视黄醇脱氢酶8），表现出视网膜异常，光加剧并与二维A酸-吡啶鎓-乙醇胺（A2E）的积累有关， 全反式视黄醛的缩合产物和有毒视黄醇的替代标记。现在我们发现这些小鼠出现了急性光诱导视网膜病变。然而，将这些动物与卵磷脂杂交：眼内缺乏类视黄醇的视黄醇酰基转移酶敲除小鼠产生的后代在用人工发色团9-顺式视黄醛灌胃之前不会表现出这种光诱导的视网膜病变。在这些条件下，A2E 没有发生显着的眼部累积。这些结果表明，这种急性光诱发的视网膜病需要游离的全反式视网膜的存在，而不是通常认为的A2E或其他类视黄醇缩合产物。有证据表明，毒性机制可能包括质膜通透性和线粒体中毒，导致半胱天冬酶激活和线粒体相关细胞死亡。这些发现进一步了解了光诱导的视网膜变性的机制。
Exposure to bright light can cause visual dysfunction and retinal photoreceptor damage in humans and experimental animals, but the mechanism(s) remain unclear. We investigated whether the retinoid cycle (i.e. the series of biochemical reactions required for vision through continuous generation of 11-cis-retinal and clearance of all-trans-retinal, respectively) might be involved. Previously, we reported that mice lacking two enzymes responsible for clearing all-trans-retinal, namely photoreceptor-specific ABCA4 (ATP-binding cassette transporter 4) and RDH8 (retinol dehydrogenase 8), manifested retinal abnormalities exacerbated by light and associated with accumulation of diretinoid-pyridinium-ethanolamine (A2E), a condensation product of all-trans-retinal and a surrogate marker for toxic retinoids. Now we show that these mice develop an acute, light-induced retinopathy. However, cross-breeding these animals with lecithin: retinol acyltransferase knock-out mice lacking retinoids within the eye produced progeny that did not exhibit such light-induced retinopathy until gavaged with the artificial chromophore, 9-cis-retinal. No significant ocular accumulation of A2E occurred under these conditions. These results indicate that this acute light-induced retinopathy requires the presence of free all-trans-retinal and not, as generally believed, A2E or other retinoid condensation products. Evidence is presented that the mechanism of toxicity may include plasma membrane permeability and mitochondrial poisoning that lead to caspase activation and mitochondria-associated cell death. These findings further understanding of the mechanisms involved in light-induced retinal degeneration.