Narayanan S P, Xu Z, Putluri N, Sreekumar A, Lemtalsi T, Caldwell R W, Caldwell R B
1] Vision Discovery Institute, Georgia Regents University, Augusta, GA, USA [2] Vascular Biology Center, Georgia Regents University, Augusta, GA, USA [3] Department of Cellular Biology and Anatomy, Georgia Regents University, Augusta, GA, USA.
1] Vision Discovery Institute, Georgia Regents University, Augusta, GA, USA [2] Vascular Biology Center, Georgia Regents University, Augusta, GA, USA.
Cell Death Dis. 2014 Feb 20;5(2):e1075. doi: 10.1038/cddis.2014.23.
Hyperoxia treatment has been known to induce neuronal and glial death in the developing central nervous system. Retinopathy of prematurity (ROP) is a devastating disease in premature infants and a major cause of childhood vision impairment. Studies indicate that, in addition to vascular injury, retinal neurons are also affected in ROP. Using an oxygen-induced retinopathy (OIR) mouse model for ROP, we have previously shown that deletion of the arginase 2 (A2) significantly reduced neuro-glial injury and improved retinal function. In the current study, we investigated the mechanism of A2 deficiency-mediated neuroprotection in the OIR retina. Hyperoxia treatment has been known to induce neuronal death in neonates. During the hyperoxia phase of OIR, a significant increase in the number of apoptotic cells was observed in the wild-type (WT) OIR retina compared with A2-deficient OIR. Mass spectrometric analysis showed alterations in polyamine metabolism in WT OIR retina. Further, increased expression level of spermine oxidase was observed in WT OIR retina, suggesting increased oxidation of polyamines in OIR retina. These changes were minimal in A2-deficient OIR retina. Treatment using the polyamine oxidase inhibitor, N, N'-bis (2, 3-butadienyl)-1, 4-butanediamine dihydrochloride, significantly improved neuronal survival during OIR treatment. Our data suggest that retinal arginase is involved in the hyperoxia-induced neuronal degeneration in the OIR model, through the regulation of polyamine metabolism.
已知高氧治疗会在发育中的中枢神经系统中诱导神经元和神经胶质细胞死亡。早产儿视网膜病变（ROP）是早产儿的一种毁灭性疾病，也是儿童视力损害的主要原因。研究表明，除血管损伤外，视网膜神经元在ROP中也会受到影响。我们先前使用氧诱导性视网膜病变（OIR）小鼠模型研究ROP时发现，精氨酸酶2（A2）的缺失显著减少了神经胶质损伤并改善了视网膜功能。在本研究中，我们调查了A2缺乏介导的OIR视网膜神经保护机制。已知高氧治疗会诱导新生儿神经元死亡。在OIR的高氧阶段，与A2缺陷型OIR相比，野生型（WT）OIR视网膜中凋亡细胞数量显著增加。质谱分析显示WT OIR视网膜中多胺代谢发生改变。此外，在WT OIR视网膜中观察到精胺氧化酶表达水平升高，表明OIR视网膜中多胺氧化增加。这些变化在A2缺陷型OIR视网膜中最小。使用多胺氧化酶抑制剂N，N'-双（2，3-丁二烯基）-1，4-丁二胺二盐酸盐进行治疗可显著提高OIR治疗期间的神经元存活率。我们的数据表明，视网膜精氨酸酶通过调节多胺代谢参与OIR模型中高氧诱导的神经元变性。
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