Research Department, King Khaled Eye Specialist Hospital, Aruba Street, P.O. Box.7191, Riyadh 11462, Kingdom of Saudi Arabia.
Mol Pharmacol. 2010 Mar;77(3):348-67. doi: 10.1124/mol.109.061366. Epub 2009 Dec 14.
Vascular endothelial growth factor (VEGF) and inducible nitric-oxide synthase (iNOS) have been implicated in ischemia-induced retinal neovascularization. Retinal ischemia has been shown to induce VEGF and iNOS expression. It has been postulated that one of the crucial consequences of iNOS expression in the ischemic retina is the inhibition of angiogenesis. Furthermore, iNOS was shown to be overexpressed in Müller cells from patients with diabetic retinopathy. YC-1, a small molecule inhibitor of hypoxia-inducible factor (HIF)-1 alpha, has been shown to inhibit iNOS expression in various tissue models. Our aim was to assess the pleiotropic effects of YC-1 in an oxygen-induced retinopathy (OIR) mouse model and evaluate its therapeutic potential in HIF-1- and iNOS-mediated retinal pathologies. Dual-injections of YC-1 into the neovascular retinas decreased the total retinopathy score, inhibited vaso-obliteration and pathologic tuft formation, and concomitantly promoted physiological retinal revascularization, compared with dimethyl sulfoxide (DMSO)-treated group. Furthermore, YC-1-treated retinas exhibited a marked increase in immunoreactivities for CD31 and von Willebrand factor and displayed significant inhibition in HIF-1alpha protein expression. Furthermore, YC-1 down-regulated VEGF, erythropoietin, endothelin-1, matrix metalloproteinase-9, and iNOS message and protein levels. When hypoxic Müller and neuoroglial cells were treated with YC-1, iNOS mRNA and protein levels were reduced in a dose-dependent fashion. We demonstrate that YC-1 inhibits pathological retinal neovascularization by exhibiting antineovascular activities, which impaired ischemia-induced expression of HIF-1 and its downstream angiogenic molecules. Furthermore, YC-1 enhanced physiological revascularization of the retinal vascular plexuses via the inhibition of iNOS mRNA and protein expressions. The pleiotropic effects of YC-1 allude to its possible use as a promising therapeutic iNOS inhibitor candidate for the treatment of retinal neovascularization.
血管内皮生长因子 (VEGF) 和诱导型一氧化氮合酶 (iNOS) 已被牵连到缺血性视网膜新生血管形成中。已经表明，视网膜缺血会诱导 VEGF 和 iNOS 的表达。有人假设，在缺血性视网膜中 iNOS 表达的一个关键后果是抑制血管生成。此外，在糖尿病性视网膜病变患者的 Müller 细胞中观察到 iNOS 过表达。YC-1 是缺氧诱导因子 (HIF)-1α 的小分子抑制剂，已被证明可抑制各种组织模型中的 iNOS 表达。我们的目的是评估 YC-1 在氧诱导的视网膜病变 (OIR) 小鼠模型中的多效作用，并评估其在 HIF-1 和 iNOS 介导的视网膜病变中的治疗潜力。与二甲亚砜 (DMSO) 处理组相比，YC-1 双注射到新生血管化视网膜中降低了总视网膜病变评分，抑制了血管闭塞和病理性簇形成，同时促进了生理性视网膜再血管化。此外，YC-1 处理的视网膜中 CD31 和血管性血友病因子的免疫反应明显增加，并且 HIF-1α 蛋白表达显著抑制。此外，YC-1 下调了 VEGF、促红细胞生成素、内皮素-1、基质金属蛋白酶-9 和 iNOS 的 mRNA 和蛋白水平。当缺氧的 Müller 和神经胶质细胞用 YC-1 处理时，iNOS mRNA 和蛋白水平呈剂量依赖性降低。我们证明，YC-1 通过表现出抗血管生成活性来抑制病理性视网膜新生血管形成，该活性损害了缺血诱导的 HIF-1 和其下游血管生成分子的表达。此外，YC-1 通过抑制 iNOS mRNA 和蛋白表达增强了视网膜血管丛的生理性再血管化。YC-1 的多效作用暗示它可能作为一种有前途的治疗性 iNOS 抑制剂候选物，用于治疗视网膜新生血管形成。
