Department of Geriatrics, Qilu Hospital of Shandong University, Jinan, Shandong Province, China; Jinan Clinical Research Center for Geriatric Medicine (202132001), Jinan, Shandong Province, China.
Department of Geriatrics, Qilu Hospital of Shandong University, Jinan, Shandong Province, China; Jinan Clinical Research Center for Geriatric Medicine (202132001), Jinan, Shandong Province, China.
Int Immunopharmacol. 2024 Dec 5;142(Pt B):113167. doi: 10.1016/j.intimp.2024.113167. Epub 2024 Sep 19.
The nicotinamide adenosine dinucleotide-dependent deacetylase Sirtuin 1 (SIRT1) has been identified as a protective factor that inhibits the activation of nucleotide-binding and oligomerization domain-, leucine-rich repeat-, and pyrin domain-containing protein 3 (NLRP3) inflammasome. However, whether pharmacological SIRT1 activators can protect retinal pigment epithelial (RPE) cells against oxidative and inflammatory injuries related to age-related macular degeneration remains to be explored.
Two small molecule specific SIRT1 activators (SRT2104 and CAY10602) were tested, with resveratrol being used as a positive control. Mouse models with sodium iodate-induced retinal degeneration were constructed. ARPE-19 cells in culture were used for in vitro experiments. The effects of SIRT1 activators on HO-induced ARPE-19 cell injury were determined by reactive oxygen species quantification, western blotting, flow cytometry and immunofluorescence staining. In vivo, the severity of retinal damage was assessed using flash electroretinography and histopathological analysis.
In vitro, SRT2104, CAY10602 and resveratrol significantly attenuated HO-induced cell death, nucleolar stress response, and reactive oxygen species accumulation. In HO-stimulated cells, SIRT1 activators reduced the level of NLRP3, inhibited the activation of caspase-1, and decreased the production of interleukin (IL)-1β and IL-18. The inhibitory effects of SIRT1 activators on caspase-1 activation and IL-1β production were blunted by SIRT1 gene silencing. In vivo, treatment with SRT2104 or CAY10602 in mice with sodium iodate-induced retinal degeneration markedly improved the retinal functions and reduced the loss of RPE cells.
Our study suggests that small molecule SIRT1 activators are effective for protection of RPE cells against oxidative stress-induced NLRP3 inflammasome activation, highlighting potential applications in the treatment of macular degeneration associated RPE dysfunctions.
烟酰胺腺嘌呤二核苷酸依赖性去乙酰化酶 Sirtuin 1（SIRT1）已被鉴定为一种保护性因子，可抑制核苷酸结合寡聚化结构域、富含亮氨酸重复和吡喃结构域蛋白 3（NLRP3）炎性体的激活。然而，是否可以通过药理学 SIRT1 激活剂来保护视网膜色素上皮（RPE）细胞免受与年龄相关性黄斑变性相关的氧化和炎症损伤，仍有待探索。
测试了两种小分子特异性 SIRT1 激活剂（SRT2104 和 CAY10602），以白藜芦醇作为阳性对照。构建了碘酸钠诱导的视网膜变性小鼠模型。体外实验采用 ARPE-19 细胞培养。通过活性氧（ROS）定量、western blot、流式细胞术和免疫荧光染色来确定 SIRT1 激活剂对 HO 诱导的 ARPE-19 细胞损伤的影响。在体内，通过闪光视网膜电图和组织病理学分析评估视网膜损伤的严重程度。
在体外，SRT2104、CAY10602 和白藜芦醇显著减轻了 HO 诱导的细胞死亡、核仁应激反应和 ROS 积累。在 HO 刺激的细胞中，SIRT1 激活剂降低了 NLRP3 的水平，抑制了半胱天冬酶-1 的激活，并减少了白细胞介素（IL）-1β和 IL-18 的产生。SIRT1 基因沉默削弱了 SIRT1 激活剂对半胱天冬酶-1 激活和 IL-1β 产生的抑制作用。在体内，SRT2104 或 CAY10602 治疗碘酸钠诱导的视网膜变性小鼠显著改善了视网膜功能并减少了 RPE 细胞的丢失。
本研究表明，小分子 SIRT1 激活剂可有效保护 RPE 细胞免受氧化应激诱导的 NLRP3 炎性体激活，这突出了其在治疗与 RPE 功能障碍相关的年龄相关性黄斑变性中的潜在应用。
