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

Jutamas Suwanpradid, Modesto Rojas, M. Ali Behzadian, R. William Caldwell, Ruth B. Caldwell

Research output: Contribution to journalArticle

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Abstract

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.

Methods and Findings: 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.

Original languageEnglish (US)
Article number110604
JournalPloS one
Volume9
Issue number11
DOIs
StatePublished - Nov 6 2014

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Hyperargininemia
hyperoxia
Arginase
arginase
Retinal Vessels
Retinal Degeneration
Hyperoxia
Oxidative stress
blood vessels
Oxidative Stress
retinal diseases
oxidative stress
Peroxynitrous Acid
Vascular System Injuries
premature birth
Retinopathy of Prematurity
Endothelial cells
Pathology
Oxygen
angiogenesis

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)

Cite this

Arginase 2 deficiency prevents oxidative stress and limits hyperoxia-induced retinal vascular degeneration. / Suwanpradid, Jutamas; Rojas, Modesto; Behzadian, M. Ali; Caldwell, R. William; Caldwell, Ruth B.

In: PloS one, Vol. 9, No. 11, 110604, 06.11.2014.

Research output: Contribution to journalArticle

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