Arginase 2 Deficiency Prevents Oxidative Stress and Limits Hyperoxia-Induced Retinal Vascular Degeneration

Abstract

BackgroundHyperoxia exposure of premature infants causes obliteration of the immature retinal microvessels, leading to a condition of proliferative vitreoretinal neovascularization termed retinopathy of prematurity (ROP). Previous work has demonstrated that the hyperoxia-induced vascular injury is mediated by dysfunction of endothelial nitric oxide synthase resulting in peroxynitrite formation. This study was undertaken to determine the involvement of the ureahydrolase enzyme arginase in this pathology.Methods and FindingsStudies were performed using hyperoxia-treated bovine retinal endothelial cells (BRE) and mice with oxygen-induced retinopathy (OIR) as experimental models of ROP. Treatment with the specific arginase inhibitor 2(S)-amino-6-boronohexanoic acid (ABH) prevented hyperoxia-induced apoptosis of BRE cells and reduced vaso-obliteration in the OIR model. Furthermore, deletion of the arginase 2 gene protected against hyperoxia-induced vaso-obliteration, enhanced physiological vascular repair, and reduced retinal neovascularization in the OIR model. Additional deletion of one copy of arginase 1 did not improve the vascular pathology. Analyses of peroxynitrite by quantitation of its biomarker nitrotyrosine, superoxide by dihydroethidium imaging and NO formation by diaminofluoroscein imaging showed that the protective actions of arginase 2 deletion were associated with blockade of superoxide and peroxynitrite formation and normalization of NOS activity.ConclusionsOur data demonstrate the involvement of arginase activity and arginase 2 expression in hyperoxia-induced vascular injury. Arginase 2 deletion prevents hyperoxia-induced retinal vascular injury by preventing NOS uncoupling resulting in decreased reactive oxygen species formation and increased nitric oxide bioavailability.

Reduced bioavailable manganese causes striatal urea cycle pathology in Huntington's disease mouse model

“…On the other hand, although both ARG1 and ARG2 are present in endothelial cells, ARG2 predominates, and arginase inhibition stimulates NO through eNOS[32] as well as increasing urea production in endothelial tissue, suggesting that a decrease of ARG2 activity could have the same effect on nNOS in neurons. In fact, deletion of ARG2 causes mice to be more susceptible to brain injury from ischemic and excitotoxic challenges[33], though the same deletion is protective against retinal vascular degeneration[34], demonstrating that even ARG2/nNOS activity may be regionally diverse, or sensitive to regional Mn accumulation.…”

Arginase: an old enzyme with new tricks

“…While the role of NO in vascular injury is well discussed, involvement of arginase in the vascular injury has only recently been appreciated. Our laboratory has found that A2 plays a key role in the hyperoxia-mediated vascular injury through a mechanism involving superoxide and peroxynitrite formation [87]. Studies using A2 deficient mice in the OIR model showed significant decreases in vaso-obliteration compared to the wild type OIR retina, demonstrating involvement of A2 in OIR-induced vascular injury.…”

Early development of the nervous system of the eutherian <i>Tupaia belangeri</i>

“…Pathological situations in which vascular contacts of horizontal cells play a role have been demonstrated in mice with oxygen-induced retinopathy, where links appear to exist between neurovascular cell injury and the arginase pathway (Suwanpradid et al, 2014). Beforehand, Ahuja et al (2005) aimed to clarify whether and how glutathione S transferase (GST) helps to protect photoreceptor cells.…”