Arginase 2 deficiency reduces hyperoxia-mediated retinal neurodegeneration through the regulation of polyamine metabolism

Abstract

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.

Adenosine A1Receptors Selectively Modulate Oxygen-Induced Retinopathy at the Hyperoxic and Hypoxic Phases by Distinct Cellular Mechanisms

“…32 We performed TUNEL analysis to determine whether the larger avascular region in WT mice at P12 was attributed to neuronal and endothelial apoptosis. Consistent with other studies, [33][34][35] TUNEL-positive signals were detected within the inner nuclear layer (INL; mainly neurons such as amacrine cells and bipolar cells) and outer nuclear layer (ONL) of the avascular area, as well as the ganglion cell layer (GCL) of both WT and A 1 R KO groups. Furthermore, TUNEL signal was detected in both INL and ONL layers but largely segregated from the CD31 þ cells (a marker for endothelium cells) with only very few TUNEL/CD31 costaining signals, indicating that apoptosis was mainly attributed to neuronal apoptosis in retina (Figs.…”

Arginase: an old enzyme with new tricks

“…Both isoforms are also expressed in retina. Prominent immunoreactivity for A1 is evident in retinal glia [64, 65] and A2 is abundant in horizontal cells, photoreceptor inner segments and cellular processes throughout the neural retina, consistent with its mitochondrial localization [66, 67]. …”

“…Partial deletion of A1 along with A2 did not confer any additional protection, suggesting that A2 is the more important isoform involved in the neurodegeneration. Further studies demonstrated increased expression of spermine oxidase together with decreases in spermine, increases in spermidine and increases in hydrogen peroxide formation in the OIR retina compared to normoxic controls, suggesting an increase in backward polyamine catabolism (Figure 4) [67]. These alterations were significantly reduced in the A2-deficient OIR retina.…”

Treatment with polyamine oxidase inhibitor reduces microglial activation and limits vascular injury in ischemic retinopathy

“…In addition, studies have shown that PAOs and acrolein can serve as novel biomarkers for diagnosis of cerebral stroke [34,35]. Our studies recently highlighted the role of polyamine metabolism in causing retinal neuronal degeneration [36]. However, the role of PAO in retinal vascular injury is unknown.…”

“…Our studies showed that hyperoxia-induced neuronal degeneration is associated with significant increase in function of PAOs and expression of SMO. This was associated with increases in spermidine and H 2 O 2 and decreases in spermine, suggesting a significant role for SMO in the neuronal injury [36]. Studies in transgenic mice overexpressing SMO in neonatal cortex have shown increased levels of H 2 O 2 and increased sensitivity to excitotoxic brain injury [38].…”