Vision Discovery Institute, Georgia Regents University, 1459 Laney Walker Boulevard, Augusta 30912, USA.
Prog Retin Eye Res. 2013 Sep;36:260-80. doi: 10.1016/j.preteyeres.2013.06.002. Epub 2013 Jul 3.
Ischemic retinopathies, such as diabetic retinopathy (DR), retinopathy of prematurity and retinal vein occlusion are a major cause of blindness in developed nations worldwide. Each of these conditions is associated with early neurovascular dysfunction. However, conventional therapies target clinically significant macula edema or neovascularization, which occur much later. Intra-ocular injections of anti-VEGF show promise in reducing retinal edema, but the effects are usually transient and the need for repeated injections increases the risk of intraocular infection. Laser photocoagulation can control pathological neovascularization, but may impair vision and in some patients the retinopathy continues to progress. Moreover, neither treatment targets early stage disease or promotes repair. This review examines the potential role of the ureahydrolase enzyme arginase as a therapeutic target for the treatment of ischemic retinopathy. Arginase metabolizes l-arginine to form proline, polyamines and glutamate. Excessive arginase activity reduces the l-arginine supply for nitric oxide synthase (NOS), causing it to become uncoupled and produce superoxide and less NO. Superoxide and NO react and form the toxic oxidant peroxynitrite. The catabolic products of polyamine oxidation and glutamate can induce more oxidative stress and DNA damage, both of which can cause cellular injury. Studies indicate that neurovascular injury during retinopathy is associated with increased arginase expression/activity, decreased NO, polyamine oxidation, formation of superoxide and peroxynitrite and dysfunction and injury of both vascular and neural cells. Furthermore, data indicate that the cytosolic isoform arginase I (AI) is involved in hyperglycemia-induced dysfunction and injury of vascular endothelial cells whereas the mitochondrial isoform arginase II (AII) is involved in neurovascular dysfunction and death following hyperoxia exposure. Thus, we postulate that activation of the arginase pathway causes neurovascular injury by uncoupling NOS and inducing polyamine oxidation and glutamate formation, thereby reducing NO and increasing oxidative stress, all of which contribute to the retinopathic process.
缺血性视网膜病变，如糖尿病视网膜病变（DR）、早产儿视网膜病变和视网膜静脉阻塞，是全球发达国家致盲的主要原因。这些疾病都与早期的神经血管功能障碍有关。然而，传统的治疗方法针对的是临床上有意义的黄斑水肿或新生血管形成，而这些通常发生在更晚期。抗血管内皮生长因子（VEGF）的眼内注射在减轻视网膜水肿方面显示出一定的前景，但效果通常是短暂的，而且需要重复注射会增加眼内感染的风险。激光光凝可以控制病理性新生血管形成，但可能会损害视力，而且在一些患者中，视网膜病变仍会继续进展。此外，这两种治疗方法都不能针对早期疾病或促进修复。本综述探讨了尿酸酶酶精氨酸酶作为治疗缺血性视网膜病变的治疗靶点的潜在作用。精氨酸酶将 l-精氨酸代谢为脯氨酸、多胺和谷氨酸。精氨酸酶活性过高会减少一氧化氮合酶（NOS）的 l-精氨酸供应，使其解偶联并产生超氧阴离子和较少的 NO。超氧阴离子和 NO 反应形成有毒的氧化氮自由基。多胺氧化和谷氨酸的代谢产物可诱导更多的氧化应激和 DNA 损伤，这两者都可能导致细胞损伤。研究表明，视网膜病变期间的神经血管损伤与精氨酸酶表达/活性增加、NO 减少、多胺氧化、超氧阴离子形成和过氧亚硝酸盐形成以及血管和神经细胞的功能障碍和损伤有关。此外，数据表明，细胞质同工酶精氨酸酶 I（AI）参与高血糖诱导的血管内皮细胞功能障碍和损伤，而线粒体同工酶精氨酸酶 II（AII）参与高氧暴露后的神经血管功能障碍和死亡。因此，我们假设，精氨酸酶途径的激活通过解偶联 NOS 并诱导多胺氧化和谷氨酸形成，从而减少 NO 和增加氧化应激，导致神经血管损伤，所有这些都有助于视网膜病变过程。
