Malondialdehyde induces autophagy dysfunction and VEGF secretion in the retinal pigment epithelium in age-related macular degeneration.
Malondialdehyde induces autophagy dysfunction and VEGF secretion in the retinal pigment epithelium in age-related macular degeneration.
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DOI：
10.1016/j.freeradbiomed.2016.02.027
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发表时间：
2016-05
影响因子：
7.4
通讯作者：
Fuxiang Ye;Hiroki Kaneko;Y. Hayashi;K. Takayama;Shiang-Jyi Hwang;Y. Nishizawa;Reona Kimoto;Yosuke Nagasak
中科院分区：
文献类型：
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作者：
Fuxiang Ye;Hiroki Kaneko;Y. Hayashi;K. Takayama;Shiang-Jyi Hwang;Y. Nishizawa;Reona Kimoto;Yosuke Nagasak
视网膜相关性黄斑变性（AMD）是发达国家致盲的主要原因，与导致脂质过氧化的氧化应激密切相关。丙二醛（MDA）是多不饱和脂肪酸（PUFA）过氧化反应的主要副产物。据报道，AMD患者的眼睛中MDA水平升高。然而，关于MDA和AMD之间的直接关系知之甚少。在这里，我们展示了MDA在AMD发病机制中的生物学重要性。我们首次证实AMD患者的眼内MDA水平显著升高。在人视网膜色素上皮细胞系ARPE-19细胞中，MDA处理诱导血管内皮生长因子（VEGF）表达改变、细胞连接破坏和自噬功能障碍，这在AMD患者的眼睛中也观察到。MDA诱导的VEGF增加被自噬-溶酶体抑制剂抑制。小鼠玻璃体内注射MDA可增加激光诱导的脉络膜新生血管（laser-CNV）体积。在小鼠模型喂养高亚油酸饮食3个月，我们发现MDA水平，自噬活性和激光CNV体积显着增加。我们的研究揭示了MDA的重要作用，它不仅是AMD发病机制相关的自噬功能障碍的标志物，也是一个致病因素。此外，较高的亚油酸饮食摄入量促进了MDA水平升高的小鼠CNV进展。
Age-related macular degeneration (AMD) is a major cause of blindness in developed countries and is closely related to oxidative stress, which leads to lipid peroxidation. Malondialdehyde (MDA) is a major byproduct of polyunsaturated fatty acid (PUFA) peroxidation. Increased levels of MDA have been reported in eyes of AMD patients. However, little is known about the direct relationship between MDA and AMD. Here we show the biological importance of MDA in AMD pathogenesis. We first confirmed that MDA levels were significantly increased in eyes of AMD patients. In ARPE-19 cells, a human retinal pigment epithelial cell line, MDA treatment induced vascular endothelial growth factor (VEGF) expression alternation, cell junction disruption, and autophagy dysfunction that was also observed in eyes of AMD patients. The MDA-induced VEGF increase was inhibited by autophagy–lysosomal inhibitors. Intravitreal MDA injection in mice increased laser-induced choroidal neovascularization (laser-CNV) volumes. In a mouse model fed a high-linoleic acid diet for 3 months, we found a significant increase in MDA levels, autophagic activity, and laser-CNV volumes. Our study revealed an important role of MDA, which acts not only as a marker but also as a causative factor of AMD pathogenesis-related autophagy dysfunction. Furthermore, higher dietary intake of linoleic acid promoted CNV progression in mice with increased MDA levels.