Department of Ophthalmology, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, China.
Proc Natl Acad Sci U S A. 2013 Feb 5;110(6):2377-82. doi: 10.1073/pnas.1221729110. Epub 2013 Jan 22.
Age-related macular degeneration (AMD) is the leading cause of registered blindness among the elderly and affects over 30 million people worldwide. It is well established that oxidative stress, inflammation, and apoptosis play critical roles in pathogenesis of AMD. In advanced wet AMD, although, most of the severe vision loss is due to bleeding and exudation of choroidal neovascularization (CNV), and it is well known that vascular endothelial growth factor (VEGF) plays a pivotal role in the growth of the abnormal blood vessels. VEGF suppression therapy improves visual acuity in AMD patients. However, there are unresolved issues, including safety and cost. Here we show that mice lacking c-Jun N-terminal kinase 1 (JNK1) exhibit decreased inflammation, reduced CNV, lower levels of choroidal VEGF, and impaired choroidal macrophage recruitment in a murine model of wet AMD (laser-induced CNV). Interestingly, we also detected a substantial reduction in choroidal apoptosis of JNK1-deficient mice. Intravitreal injection of a pan-caspase inhibitor reduced neovascularization in the laser-induced CNV model, suggesting that apoptosis plays a role in laser-induced pathological angiogenesis. Intravitreal injection of a specific JNK inhibitor decreased choroidal VEGF expression and reduced pathological CNV. These results suggest that JNK1 plays a key role in linking oxidative stress, inflammation, macrophage recruitment apoptosis, and VEGF production in wet AMD and pharmacological JNK inhibition offers a unique and alternative avenue for prevention and treatment of AMD.
年龄相关性黄斑变性（AMD）是老年人致盲的主要原因，全球有超过 3000 万人受到影响。氧化应激、炎症和细胞凋亡在 AMD 的发病机制中起着关键作用，这一点已得到充分证实。然而，在晚期湿性 AMD 中，尽管大多数严重的视力丧失是由于脉络膜新生血管（CNV）的出血和渗出引起的，但众所周知，血管内皮生长因子（VEGF）在异常血管的生长中起着关键作用。VEGF 抑制疗法可改善 AMD 患者的视力。然而，仍存在一些未解决的问题，包括安全性和成本。在这里，我们展示了缺乏 c-Jun N-末端激酶 1（JNK1）的小鼠在湿性 AMD 的小鼠模型（激光诱导的 CNV）中表现出炎症减少、CNV 减少、脉络膜 VEGF 水平降低以及脉络膜巨噬细胞募集受损。有趣的是，我们还检测到 JNK1 缺陷小鼠脉络膜细胞凋亡明显减少。玻璃体内注射泛半胱天冬酶抑制剂可减少激光诱导的 CNV 模型中的新生血管形成，表明细胞凋亡在激光诱导的病理性血管生成中起作用。玻璃体内注射特异性 JNK 抑制剂可降低脉络膜 VEGF 表达并减少病理性 CNV。这些结果表明 JNK1 在连接氧化应激、炎症、巨噬细胞募集、细胞凋亡和湿性 AMD 中的 VEGF 产生方面起着关键作用，而药理学 JNK 抑制为 AMD 的预防和治疗提供了独特的替代途径。
