Department of Biochemistry, CSIR-Central Food Technological Research Institute, Mysore, 570020, Karnataka, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201002, India.
Department of Biochemistry, CSIR-Central Food Technological Research Institute, Mysore, 570020, Karnataka, India.
Exp Eye Res. 2021 May;206:108555. doi: 10.1016/j.exer.2021.108555. Epub 2021 Mar 28.
Breakdown of outer blood-retina barrier (BRB) has been associated with the pathogenesis of diabetic retinopathy (DR) and diabetic macular edema (DME). Vascular endothelial growth factor (VEGF) might play a detrimental role in the pathogenesis of DME, a major clinical manifestation of DR. In the present study, we investigated the inhibitory mechanism of astaxanthin on VEGF and its upstream signaling pathways under in vitro and in vivo conditions. Astaxanthin has been observed to downregulate VEGF expression under hyperglycemic (HG) and CoCl induced hypoxic conditions in ARPE-19 cells. There were compelling pieces of evidence for the involvement of transcription factors like HIF1α and XBP1 in the upregulation of VEGF under HG and hypoxic conditions. Thus, we investigated the role of astaxanthin in the expression and nuclear translocation of HIF1α and XBP1. The activation and translocation of HIF1α and XBP1 induced by HG or CoCl conditions were hindered by astaxanthin. Additionally, treatment with HIF1α siRNA and IRE1 inhibitor STF-083010 also inhibited the expression of VEGF induced by HG and CoCl conditions. These results indicated that the anti-VEGF property of astaxanthin might be associated with the downregulation of HIF1α and XBP1. Furthermore, astaxanthin mitigated the enhanced migration of retinal pigment epithelial (RPE) cells under DR conditions. As well, astaxanthin protected disorganization of zona occludin-1 (ZO-1) tight junction protein in RPE and reduced HG or hypoxic induced permeability of RPE cells. In streptozotocin-induced diabetic rat model, astaxanthin reduced the expression of HIF1α, XBP1, and VEGF as well as protected the abnormalities in the retinal layers induced by diabetes condition. Thus, astaxanthin may be used as a potential nutraceutical to prevent or treat retinal dysfunction in diabetic patients.
外血视网膜屏障（BRB）的破坏与糖尿病性视网膜病变（DR）和糖尿病性黄斑水肿（DME）的发病机制有关。血管内皮生长因子（VEGF）可能在 DME 的发病机制中发挥有害作用，DME 是 DR 的主要临床表现。在本研究中，我们在体外和体内条件下研究了虾青素对 VEGF 及其上游信号通路的抑制机制。在 ARPE-19 细胞中，虾青素在高血糖（HG）和 CoCl 诱导的缺氧条件下观察到下调 VEGF 的表达。有强有力的证据表明，转录因子如 HIF1α 和 XBP1 在 HG 和缺氧条件下上调 VEGF。因此，我们研究了虾青素在 VEGF 表达和核转位中 HIF1α 和 XBP1 的作用。HG 或 CoCl 条件下诱导的 HIF1α 和 XBP1 的激活和易位被虾青素所阻碍。此外，用 HIF1α siRNA 和 IRE1 抑制剂 STF-083010 处理也抑制了 HG 和 CoCl 条件下诱导的 VEGF 的表达。这些结果表明，虾青素的抗 VEGF 特性可能与 HIF1α 和 XBP1 的下调有关。此外，虾青素减轻了 DR 条件下视网膜色素上皮（RPE）细胞迁移的增强。同样，虾青素保护 RPE 中闭锁蛋白-1（ZO-1）紧密连接蛋白的紊乱，并降低 RPE 细胞的 HG 或缺氧诱导的通透性。在链脲佐菌素诱导的糖尿病大鼠模型中，虾青素降低了 HIF1α、XBP1 和 VEGF 的表达，并保护了糖尿病状态引起的视网膜层异常。因此，虾青素可用作预防或治疗糖尿病患者视网膜功能障碍的潜在营养保健品。
