Wang Kai, Chen Yong-Syuan, Chien Hsiang-Wen, Chiou Hui-Ling, Yang Shun-Fa, Hsieh Yi-Hsien
Department of Ophthalmology, Cathay General Hospital, Taipei, Taiwan.
Departments of Ophthalmology, Sijhih Cathay General Hospital, New Taipei City, Taiwan.
Cell Biosci. 2022 Aug 19;12(1):133. doi: 10.1186/s13578-022-00879-3.
Age-related macular degeneration (AMD) leads to gradual central vision loss and eventual irreversible blindness. Melatonin, an endogenous hormone, exhibits anti-inflammatory and antitumor effects; however, the role it plays in AMD remains unclear. Herein, we investigated the anti-AMD molecular mechanism of melatonin after sodium iodate (NaIO3) treatment of ARPE-19 cells in vitro and in animal models with the goal of improving the therapeutic effect.
The in vitro results showed that melatonin protected against NaIO-induced cell viability decline, mitochondrial dysfunction and apoptosis in ARPE-19 cells, and melatonin also alleviated NaIO-induced reactive oxygen species (ROS) production, mitochondrial dysfunction and mitophagy activation. Melatonin reduced NaIO-induced mitophagy activation through HIF-1α-targeted BNIP3/LC3B transcription, whereas ROS inhibition realized with N-acetylcysteine (NAC, a ROS inhibitor) combined with melatonin reduced the effect of NaIO on mitophagy. An animal model of AMD was established to confirm the in vitro data. Mouse tail vein injection of NaIO and melatonin was associated with enhanced repair of retinal layers within 7 days, as observed by optical coherence tomography (OCT) and hematoxylin and eosin (H&E) staining. A reduction in BNIP3 and HIF-1α levels, as determined by immunohistochemistry (IHC) assay, was also observed.
These results indicate that melatonin attenuated NaIO-induced mitophagy of ARPE-19 cells via reduction in ROS-mediated HIF-1α targeted BNIP3/LC3B signaling in vitro and in vivo. Melatonin may be a potential therapeutic drug in the treatment of AMD.
年龄相关性黄斑变性（AMD）会导致逐渐的中心视力丧失并最终导致不可逆的失明。褪黑素是一种内源性激素，具有抗炎和抗肿瘤作用；然而，其在AMD中所起的作用仍不清楚。在此，我们研究了褪黑素在体外对碘酸钠（NaIO₃）处理的ARPE - 19细胞以及在动物模型中的抗AMD分子机制，旨在提高治疗效果。
体外实验结果表明，褪黑素可保护ARPE - 19细胞免受NaIO诱导的细胞活力下降、线粒体功能障碍和凋亡，并且褪黑素还减轻了NaIO诱导的活性氧（ROS）产生、线粒体功能障碍和线粒体自噬激活。褪黑素通过靶向HIF - 1α的BNIP3/LC3B转录减少NaIO诱导的线粒体自噬激活，而用N - 乙酰半胱氨酸（NAC，一种ROS抑制剂）与褪黑素联合实现的ROS抑制降低了NaIO对线粒体自噬的影响。建立了AMD动物模型以证实体外实验数据。通过光学相干断层扫描（OCT）和苏木精 - 伊红（H&E）染色观察到，小鼠尾静脉注射NaIO和褪黑素与7天内视网膜层修复增强有关。免疫组织化学（IHC）分析还观察到BNIP3和HIF - 1α水平降低。
这些结果表明，褪黑素在体外和体内通过减少ROS介导的靶向HIF - 1α的BNIP3/LC3B信号传导来减轻NaIO诱导的ARPE - 19细胞线粒体自噬。褪黑素可能是治疗AMD的一种潜在治疗药物。
