Arginase 2 deficiency prevents oxidative stress and limits hyperoxia-induced retinal vascular degeneration.
BACKGROUND
Hyperoxia 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.


RESULTS
Studies 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.


CONCLUSIONS
Our 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.
Vascular Biology Center, Georgia Regents University, Augusta, Georgia, United States of America; Culver Vision Discovery Institute, Georgia Regents University, Augusta, Georgia, United States of America.
Jutamas
J
Suwanpradid
Vascular Biology Center, Georgia Regents University, Augusta, Georgia, United States of America; Culver Vision Discovery Institute, Georgia Regents University, Augusta, Georgia, United States of America; Department of Pharmacology and Toxicology, Department of Cellular Biology & Anatomy, Georgia Regents University, Augusta, Georgia, United States of America.
Modesto
M
Rojas
Vascular Biology Center, Georgia Regents University, Augusta, Georgia, United States of America.
M Ali
MA
Behzadian
Culver Vision Discovery Institute, Georgia Regents University, Augusta, Georgia, United States of America; Department of Pharmacology and Toxicology, Department of Cellular Biology & Anatomy, Georgia Regents University, Augusta, Georgia, United States of America.
R William
RW
Caldwell
Vascular Biology Center, Georgia Regents University, Augusta, Georgia, United States of America; Culver Vision Discovery Institute, Georgia Regents University, Augusta, Georgia, United States of America; Charlie Norwood VA Medical Center, Augusta, Georgia, United States of America.
Ruth B
RB
Caldwell
D000818:Animals; D017209:Apoptosis; D001119:Arginase / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D002417:Cattle; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D006801:Humans; D018496:Hyperoxia / Q000150:complications*; D007231:Infant, Newborn; D051379:Mice; D009569:Nitric Oxide / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects / Q000235:genetics*; D030421:Peroxynitrous Acid / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D012160:Retina / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D012162:Retinal Degeneration / Q000209:etiology / Q000235:genetics / Q000473:pathology / Q000517:prevention & control*; D015861:Retinal Neovascularization / Q000209:etiology / Q000235:genetics / Q000473:pathology / Q000517:prevention & control*; D012178:Retinopathy of Prematurity / Q000235:genetics / Q000473:pathology / Q000517:prevention & control*; D013481:Superoxides / Q000378:metabolism
D017382:Reactive Oxygen Species; D013481:Superoxides; D030421:Peroxynitrous Acid; D009569:Nitric Oxide; D052250:Nitric Oxide Synthase Type III; C481673:Arg2 protein, mouse; D001119:Arginase