Department of Oral Biology and Anatomy, Medical College of Georgia, Augusta, Georgia, USA.
Diabetes. 2011 Feb;60(2):614-24. doi: 10.2337/db10-0008. Epub 2011 Jan 12.
Arachidonic acid is metabolized by 12-lipoxygenase (12-LOX) to 12-hydroxyeicosatetraenoic acid (12-HETE) and has an important role in the regulation of angiogenesis and endothelial cell proliferation and migration. The goal of this study was to investigate whether 12-LOX plays a role in retinal neovascularization (NV).
Experiments were performed using retinas from a murine model of oxygen-induced ischemic retinopathy (OIR) that was treated with and without the LOX pathway inhibitor, baicalein, or lacking 12-LOX. We also analyzed vitreous samples from patients with and without proliferative diabetic retinopathy (PDR). Western blotting and RT-PCR were used to assess the expression of 12-LOX, vascular endothelial growth factor (VEGF), and pigment epithelium-derived factor (PEDF). Liquid chromatography-mass spectrometry was used to assess the amounts of HETEs in the murine retina and human vitreous samples. The effects of 12-HETE on VEGF and PEDF expression were evaluated in Müller cells (rMCs), primary mouse retinal pigment epithelial cells, and astrocytes.
Retinal NV during OIR was associated with increased 12-LOX expression and 12-, 15-, and 5-HETE production. The amounts of HETEs also were significantly higher in the vitreous of diabetic patients with PDR. Retinal NV was markedly abrogated in mice treated with baicalein or mice lacking 12-LOX. This was associated with decreased VEGF expression and restoration of PEDF levels. PEDF expression was reduced in 12-HETE-treated rMCs, astrocytes, and the retinal pigment epithelium. Only rMCs and astrocytes showed increased VEGF expression by 12-HETE.
12-LOX and its product HETE are important regulators of retinal NV through modulation of VEGF and PEDF expression and could provide a new therapeutic target to prevent and treat ischemic retinopathy.
花生四烯酸通过 12-脂氧合酶（12-LOX）代谢为 12-羟基二十碳四烯酸（12-HETE），在调节血管生成和内皮细胞增殖及迁移方面发挥着重要作用。本研究旨在探讨 12-LOX 是否在视网膜新生血管化（NV）中发挥作用。
本研究采用氧诱导缺血性视网膜病变（OIR）小鼠模型的视网膜进行实验，模型分为加用和未加用脂氧合酶途径抑制剂黄芩素以及缺乏 12-LOX 的组别。我们还分析了伴有和不伴有增生性糖尿病视网膜病变（PDR）的患者的玻璃体液样本。Western blot 和 RT-PCR 用于评估 12-LOX、血管内皮生长因子（VEGF）和色素上皮衍生因子（PEDF）的表达。液质联用分析用于评估小鼠视网膜和人玻璃体液样本中 HETEs 的含量。12-HETE 对 Müller 细胞（rMCs）、原代小鼠视网膜色素上皮细胞和星形胶质细胞中 VEGF 和 PEDF 表达的影响也进行了评估。
OIR 期间的视网膜 NV 与 12-LOX 表达增加以及 12、15 和 5-HETE 产生有关。伴有 PDR 的糖尿病患者玻璃体液中 HETEs 的含量也明显升高。用黄芩素处理或缺乏 12-LOX 的小鼠的视网膜 NV 明显减少。这与 VEGF 表达降低和 PEDF 水平恢复有关。12-HETE 处理的 rMCs、星形胶质细胞和视网膜色素上皮细胞中 PEDF 表达减少。仅 rMCs 和星形胶质细胞的 VEGF 表达被 12-HETE 增加。
12-LOX 及其产物 HETE 是通过调节 VEGF 和 PEDF 表达来调节视网膜 NV 的重要调节剂，为预防和治疗缺血性视网膜病变提供了新的治疗靶点。
Zotero 插件
