Arginase in retinopathy.
Arginase in retinopathy.
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DOI：
10.1016/j.preteyeres.2013.06.002
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发表时间：
2013-09
影响因子：
17.8
通讯作者：
Caldwell RB
中科院分区：
文献类型：
--
作者：
Narayanan SP;Rojas M;Suwanpradid J;Toque HA;Caldwell RW;Caldwell RB
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世界发达国家致盲的主要原因。这些疾病中的每一种都与早期神经血管功能障碍有关。然而，常规疗法针对临床上显著的黄斑水肿或新血管形成，其发生得晚得多。眼内注射抗VEGF显示出减少视网膜水肿的前景，但效果通常是短暂的，并且重复注射的需要增加了眼内感染的风险。激光光凝可以控制病理性新生血管，但可能损害视力，并且在一些患者中视网膜病变继续进展。此外，这两种治疗都不能针对早期疾病或促进修复。本文综述了尿素水解酶作为治疗缺血性视网膜病变的治疗靶点的潜在作用。精氨酸酶代谢L-精氨酸形成脯氨酸、多胺和谷氨酸。过量的精氨酸酶活性降低了一氧化氮合酶（NOS）的L-精氨酸供应，导致其解偶联并产生超氧化物和更少的NO。超氧化物和NO反应并形成有毒的氧化剂过氧亚硝酸盐。多胺氧化和谷氨酸的分解代谢产物可诱导更多的氧化应激和DNA损伤，这两者都可引起细胞损伤。研究表明，视网膜病变过程中的神经血管损伤与血管酶表达/活性增加、NO、多胺氧化减少、超氧化物和过氧亚硝酸盐的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，胞质异构体脱氢酶I（AI）参与高血糖诱导的功能障碍和血管内皮细胞损伤，而线粒体异构体脱氢酶II（AII）参与神经血管功能障碍和高氧暴露后死亡。因此，我们推测，激活的nNOS途径引起神经血管损伤解偶联NOS和诱导多胺氧化和谷氨酸形成，从而减少NO和增加氧化应激，所有这些都有助于视网膜病变的过程。
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. Intraocular 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.
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