title: 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.
authors.affiliation: 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.
authors.forename: S P
authors.initials: SP
authors.lastname: Narayanan
authors.affiliation: 1] Vision Discovery Institute, Georgia Regents University, Augusta, GA, USA [2] Vascular Biology Center, Georgia Regents University, Augusta, GA, USA.
authors.forename: Z
authors.initials: Z
authors.lastname: Xu
authors.affiliation: Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA.
authors.forename: N
authors.initials: N
authors.lastname: Putluri
authors.affiliation: Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA.
authors.forename: A
authors.initials: A
authors.lastname: Sreekumar
authors.affiliation: 1] Vision Discovery Institute, Georgia Regents University, Augusta, GA, USA [2] Vascular Biology Center, Georgia Regents University, Augusta, GA, USA.
authors.forename: T
authors.initials: T
authors.lastname: Lemtalsi
authors.affiliation: Department of Pharmacology and Toxicology, Georgia Regents University, Augusta, GA, USA.
authors.forename: R W
authors.initials: RW
authors.lastname: Caldwell
authors.affiliation: 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 [4] Charlie Norwood VA Medical Center, Augusta, GA, USA.
authors.forename: R B
authors.initials: RB
authors.lastname: Caldwell
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis / Q000187:drug effects; D001119:Arginase / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology; D020162:Hyperargininemia / Q000150:complications* / Q000201:enzymology / Q000235:genetics; D018496:Hyperoxia / Q000150:complications* / Q000201:enzymology / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D018696:Neuroprotective Agents / Q000494:pharmacology; D000587:Oxidoreductases Acting on CH-NH Group Donors / Q000037:antagonists & inhibitors / Q000378:metabolism; D011073:Polyamines / Q000378:metabolism*; D012162:Retinal Degeneration / Q000201:enzymology / Q000209:etiology / Q000235:genetics / Q000473:pathology / Q000517:prevention & control*; D055351:Retinal Neurons / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology; D012178:Retinopathy of Prematurity / Q000201:enzymology / Q000209:etiology / Q000235:genetics / Q000473:pathology / Q000517:prevention & control*; D015398:Signal Transduction; D013997:Time Factors; D000097667:Polyamine Oxidase
chemical_list: D001119:Arginase; D004791:Enzyme Inhibitors; D018696:Neuroprotective Agents; D000587:Oxidoreductases Acting on CH-NH Group Donors; D011073:Polyamines; D000097667:Polyamine Oxidase; C481673:Arg2 protein, mouse