Department of Ophthalmology, the Third Medical Center, Chinese PLA General Hospital, Beijing, China.
Department of Ophthalmology, Eye Institute of China PLA, Xijing Hospital, Fourth Military Medical University, Xi'an, China.
Exp Eye Res. 2023 Aug;233:109547. doi: 10.1016/j.exer.2023.109547. Epub 2023 Jun 20.
Despite decades of researches, the underlying mechanism of retinopathy of prematurity (ROP) remains unclear. The role of Sirt2, which is involved in both angiogenesis and inflammation, both pivotal in ROP, was investigated in an animal model of ROP known as oxygen-induced retinopathy (OIR). Our study found that Sirt2 was overexpressed and colocalized with microglia in OIR. Furthermore, it demonstrated that the level of Sirt2 was upregulated in hypoxia microglia BV-2 in vitro. Subsequently, our results elucidated that administration of the Sirt2 antagonist AGK2 attenuated the avascular and neovascular area and downregulated the expression of IGF-1. The phosphorylation of Akt and the expression of IGF-1 were upregulated in hypoxia BV-2 and conditional media collected from BV-2 under hypoxia promoted the migration and tube formation of retinal capillary endothelial cells, which were suppressed with AGK2. Notably, our findings are the first to demonstrate the deleterious role of Sirt2 in ROP, as Sirt2 inhibition led to the downregulation of Akt/IGF-1 and ameliorated vasculopathy, ultimately improving visual function. These results suggest that Sirt2 may be a promising therapeutic target for ROP.
尽管经过了几十年的研究，早产儿视网膜病变（ROP）的潜在机制仍不清楚。Sirt2 参与了血管生成和炎症，这两者在 ROP 中都至关重要，我们在一种称为氧诱导视网膜病变（OIR）的 ROP 动物模型中研究了 Sirt2 的作用。我们的研究发现，Sirt2 在 OIR 中过度表达并与小胶质细胞共定位。此外，它表明 Sirt2 的水平在体外低氧微环境中的 BV-2 小胶质细胞中上调。随后，我们的结果阐明了 Sirt2 拮抗剂 AGK2 的给药减轻了无血管和新生血管区域，并下调了 IGF-1 的表达。缺氧 BV-2 中的 Akt 磷酸化和 IGF-1 的表达上调，并且从缺氧条件下的 BV-2 收集的条件培养基促进了视网膜毛细血管内皮细胞的迁移和管形成，而 AGK2 抑制了这些过程。值得注意的是，我们的研究结果首次证明了 Sirt2 在 ROP 中的有害作用，因为 Sirt2 抑制导致 Akt/IGF-1 下调，并改善了血管病变，最终改善了视觉功能。这些结果表明 Sirt2 可能是 ROP 的一个有前途的治疗靶点。
