Department of Ophthalmology, Medical University of South Carolina, Charleston, South Carolina, USA.
J Ocul Pharmacol Ther. 2024 Jul-Aug;40(6):397-406. doi: 10.1089/jop.2023.0163. Epub 2024 Apr 12.
Previously, we identified increased retinal degeneration and cytokine response in a mouse model of dry age-related macular degeneration (AMD) in the presence of systemic inflammation from rheumatoid arthritis (RA). Histone deacetylases (HDACs) regulate cytokine production by reducing acetylation and are found to be dysregulated in inflammatory diseases, including RA and AMD. Therefore, this current study investigates the effect of HDAC inhibition on AMD progression in the presence of systemic inflammation. Collagen induced arthritis (CIA) was induced in C57BL6J mice, followed by sodium iodate (NaIO)-induced retinal degeneration. Mice were treated with a selective HDAC class I inhibitor, MS-275, and retinal structure [optical coherence tomography (OCT)], function (electroretinography), and molecular changes quantitative real-time polymerase chain reaction (RT-qPCR, Western Blot) were assessed. NaIO retinal damage was diminished in CIA mice treated with MS-275 ( ≤ 0.05). While no significant difference was observed in retinal pigment epithelium (RPE) function, a trend in increased c-wave amplitude was detected in CIA + NaIO mice treated with MS-275. Finally, we identified decreased , , and expression in CIA + NaIO mouse RPE/choroid when treated with MS-275 ( ≤ 0.05). Our data demonstrate that HDAC inhibition can reduce the additive effect of NaIO-induced retinal degeneration in the presence of systemic inflammation by CIA as measured by OCT analysis. In addition, HDAC inhibition in CIA + NaIO treated mice resulted in reduced cytokine production. These findings are highly innovative and provide additional support to the therapeutic potential of HDAC inhibitors for dry AMD treatment.
此前，我们在类风湿关节炎（RA）引起的系统性炎症存在的情况下，在干性年龄相关性黄斑变性（AMD）的小鼠模型中发现视网膜变性和细胞因子反应增加。组蛋白去乙酰化酶（HDACs）通过减少乙酰化来调节细胞因子的产生，并且在包括 RA 和 AMD 在内的炎症性疾病中发现失调。因此，本研究调查了在系统性炎症存在的情况下，HDAC 抑制对 AMD 进展的影响。 在 C57BL6J 小鼠中诱导胶原诱导性关节炎（CIA），然后用碘酸钠（NaIO）诱导视网膜变性。用选择性 HDAC 类 I 抑制剂 MS-275 治疗小鼠，并评估视网膜结构[光学相干断层扫描（OCT）]、功能（视网膜电图）和分子变化[实时定量聚合酶链反应（RT-qPCR）、Western Blot]。 MS-275 治疗 CIA 小鼠可减轻 NaIO 视网膜损伤（≤0.05）。虽然在视网膜色素上皮（RPE）功能中未观察到显着差异，但在 CIA + NaIO 小鼠中检测到 MS-275 治疗时 c 波幅度增加的趋势。最后，当 CIA + NaIO 小鼠的 RPE/脉络膜用 MS-275 治疗时，我们发现 、 和 的表达降低（≤0.05）。 我们的数据表明，通过 OCT 分析，HDAC 抑制可减少 CIA 存在下 NaIO 诱导的视网膜变性的附加效应。此外，在 CIA + NaIO 治疗的小鼠中抑制 HDAC 导致细胞因子产生减少。这些发现具有创新性，为 HDAC 抑制剂治疗干性 AMD 的治疗潜力提供了额外的支持。
