Division of Science and Engineering, Iwate University, Morioka 020-8551, Japan.
Departments of Ophthalmology University of Tennessee Health Science Center, Memphis, TN 38163.
J Lipid Res. 2019 Jan;60(1):30-43. doi: 10.1194/jlr.M082198. Epub 2018 Nov 9.
Over 11 million people in the United States alone have some form of age-related macular degeneration (AMD). Oxidative stress, cell death, and the degeneration of retinal pigment epithelial (RPE) cells contribute to AMD pathology. Recent evidence suggests that ceramide (Cer), a cellular sphingolipid mediator that acts as a second messenger to induce apoptosis, might play a role in RPE cell death. The lysosomal breakdown of Cer by acid ceramidase [-acylsphingosine amidohydrolase (ASAH)1] into sphingosine (Sph) is the major source for Sph 1-phosphate production, which has an opposing role to Cer and provides cytoprotection. Here, we investigated the role of Cer in human RPE-derived ARPE19 cells under hydrogen peroxide-induced oxidative stress, and show that Cer and hexosyl-Cer levels increase in the oxidatively stressed ARPE19 cells, which can be prevented by overexpression of lysosomal ASAH1. This study demonstrates that oxidative stress generates sphingolipid death mediators in retinal cells and that induction of ASAH1 could rescue retinal cells from oxidative stress by hydrolyzing excess Cers.
仅在美国，就有超过 1100 万人患有某种与年龄相关的黄斑变性（AMD）。氧化应激、细胞死亡和视网膜色素上皮（RPE）细胞的退化导致 AMD 发病机制。最近的证据表明，神经酰胺（Cer），一种作为第二信使诱导细胞凋亡的细胞鞘脂介质，可能在 RPE 细胞死亡中发挥作用。酸性神经酰胺酶[-酰基鞘氨醇酰胺水解酶（ASAH）1]将 Cer 分解为神经酰胺（Sph），这是 Sph1-磷酸产生的主要来源，它与 Cer 作用相反，提供细胞保护。在这里，我们研究了 Cer 在过氧化氢诱导的氧化应激下对人 RPE 衍生的 ARPE19 细胞的作用，并表明在氧化应激的 ARPE19 细胞中 Cer 和己糖神经酰胺（Hex-Cer）水平增加，这可以通过过表达溶酶体 ASAH1 来预防。这项研究表明，氧化应激会在视网膜细胞中产生鞘脂死亡介质，而诱导 ASAH1 可以通过水解多余的 Cer 来挽救视网膜细胞免受氧化应激。
