Methylglyoxal induces cell death through endoplasmic reticulum stress-associated ROS production and mitochondrial dysfunction.
Methylglyoxal induces cell death through endoplasmic reticulum stress-associated ROS production and mitochondrial dysfunction.
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DOI：
10.1111/jcmm.12893
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发表时间：
2016-09
影响因子：
5.3
通讯作者：
Lin WW
中科院分区：
文献类型：
--
作者：
Chan CM;Huang DY;Huang YP;Hsu SH;Kang LY;Shen CM;Lin WW
糖尿病视网膜病变（DR）和年龄相关性黄斑变性（AMD）是发达国家获得性失明的两个重要主要原因。由于晚期糖基化终产物（AGEs）在视网膜色素上皮（RPE）细胞中的积累在DR和AMD中起着重要作用，并且AGEs中的甲基乙二醛（MGO）对蛋白质结构和功能产生不可逆的影响，因此了解MGO诱导RPE细胞死亡的潜在机制至关重要。本研究以ARPE-19为细胞模型，揭示了MGO通过非半胱天冬酶依赖的方式诱导RPE细胞死亡，其依赖于活性氧（ROS）的形成、线粒体膜电位（MMP）的丧失、细胞内钙离子升高和内质网（ER）应激反应。ROS生成的抑制可以逆转MGO诱导的ROS生成、MMP损失、细胞内钙升高和细胞死亡。此外，钙池操纵的钙通道抑制剂MRS 1845和YM-58483，而不是肌醇1，4，5-三磷酸（IP 3）受体抑制剂xestospongin C，可以阻断MGO诱导的ROS产生，MMP损失和持续的细胞内钙增加ARPE-19细胞。最后，salubrinal和4-PBA对ER应激的抑制可以减少MGO诱导的细胞内事件和细胞死亡。因此，我们的数据表明，MGO可以降低RPE细胞活力，这是由于ER应激依赖性细胞内ROS产生、MMP损失和细胞内钙增加所致。由于MGO是AMD玻璃疣的组成成分之一，是DR中AGEs的加合物，因此本研究为深入了解AMD和DR的分子发病机制和治疗干预提供了有价值的信息。
Diabetic retinopathy (DR) and age‐related macular degeneration (AMD) are two important leading causes of acquired blindness in developed countries. As accumulation of advanced glycation end products (AGEs) in retinal pigment epithelial (RPE) cells plays an important role in both DR and AMD, and the methylglyoxal (MGO) within the AGEs exerts irreversible effects on protein structure and function, it is crucial to understand the underlying mechanism of MGO‐induced RPE cell death. Using ARPE‐19 as the cell model, this study revealed that MGO induces RPE cell death through a caspase‐independent manner, which relying on reactive oxygen species (ROS) formation, mitochondrial membrane potential (MMP) loss, intracellular calcium elevation and endoplasmic reticulum (ER) stress response. Suppression of ROS generation can reverse the MGO‐induced ROS production, MMP loss, intracellular calcium increase and cell death. Moreover, store‐operated calcium channel inhibitors MRS1845 and YM‐58483, but not the inositol 1,4,5‐trisphosphate (IP3) receptor inhibitor xestospongin C, can block MGO‐induced ROS production, MMP loss and sustained intracellular calcium increase in ARPE‐19 cells. Lastly, inhibition of ER stress by salubrinal and 4‐PBA can reduce the MGO‐induced intracellular events and cell death. Therefore, our data indicate that MGO can decrease RPE cell viability, resulting from the ER stress‐dependent intracellular ROS production, MMP loss and increased intracellular calcium increase. As MGO is one of the components of drusen in AMD and is the AGEs adduct in DR, this study could provide a valuable insight into the molecular pathogenesis and therapeutic intervention of AMD and DR.