title: Arginase 2 promotes neurovascular degeneration during ischemia/reperfusion injury.
abstract: Retinal ischemia is a major cause of visual impairment and blindness and is involved in various disorders including diabetic retinopathy, glaucoma, optic neuropathies and retinopathy of prematurity. Neurovascular degeneration is a common feature of these pathologies. Our lab has previously reported that the ureahydrolase arginase 2 (A2) is involved in ischemic retinopathies. Here, we are introducing A2 as a therapeutic target to prevent neurovascular injury after retinal ischemia/reperfusion (I/R) insult. Studies were performed with mice lacking both copies of A2 (A2-/-) and wild-type (WT) controls (C57BL6J). I/R insult was conducted on the right eye and the left eye was used as control. Retinas were collected for analysis at different times (3 h-4 week after injury). Neuronal and microvascular degeneration were evaluated using NeuN staining and vascular digests, respectively. Glial activation was evaluated by glial fibrillary acidic protein expression. Necrotic cell death was studied by propidium iodide labeling and western blot for RIP-3. Arginase expression was determined by western blot and quantitative RT-PCR. Retinal function was determined by electroretinography (ERG). A2 mRNA and protein levels were increased in WT I/R. A2 deletion significantly reduced ganglion cell loss and microvascular degeneration and preserved retinal morphology after I/R. Glial activation, reactive oxygen species formation and cell death by necroptosis were significantly reduced by A2 deletion. ERG showed improved positive scotopic threshold response with A2 deletion. This study shows for the first time that neurovascular injury after retinal I/R is mediated through increased expression of A2. Deletion of A2 was found to be beneficial in reducing neurovascular degeneration after I/R.
authors.affiliation: Vascular Biology Center, Medical College of Georgia, Augusta University, Augusta, GA, USA.|Vision Discovery Institute, Augusta University, Augusta, GA, USA.|Charlie Norwood VA Medical Center, Augusta, GA, USA.
authors.forename: Esraa
authors.initials: E
authors.lastname: Shosha
authors.affiliation: Vascular Biology Center, Medical College of Georgia, Augusta University, Augusta, GA, USA.|Vision Discovery Institute, Augusta University, Augusta, GA, USA.|Charlie Norwood VA Medical Center, Augusta, GA, USA.
authors.forename: Zhimin
authors.initials: Z
authors.lastname: Xu
authors.affiliation: Department of Ophthalmology, Asahikawa Medical University, Asahikawa, Japan.
authors.forename: Harumasa
authors.initials: H
authors.lastname: Yokota
authors.affiliation: Vision Discovery Institute, Augusta University, Augusta, GA, USA.|Department of Ophthalmology, Augusta University, Augusta, GA, USA.
authors.forename: Alan
authors.initials: A
authors.lastname: Saul
authors.affiliation: Vascular Biology Center, Medical College of Georgia, Augusta University, Augusta, GA, USA.|Vision Discovery Institute, Augusta University, Augusta, GA, USA.|Charlie Norwood VA Medical Center, Augusta, GA, USA.
authors.forename: Modesto
authors.initials: M
authors.lastname: Rojas
authors.affiliation: Department of Pharmacology and Toxicology, Augusta University, Augusta, GA, USA.
authors.forename: R William
authors.initials: RW
authors.lastname: Caldwell
authors.affiliation: Vascular Biology Center, Medical College of Georgia, Augusta University, Augusta, GA, USA.|Vision Discovery Institute, Augusta University, Augusta, GA, USA.|Charlie Norwood VA Medical Center, Augusta, GA, USA.
authors.forename: Ruth B
authors.initials: RB
authors.lastname: Caldwell
authors.affiliation: Vision Discovery Institute, Augusta University, Augusta, GA, USA.|Department of Occupational Therapy, College of Allied Health Sciences, Augusta University, Augusta, GA, USA.
authors.forename: S Priya
authors.initials: SP
authors.lastname: Narayanan
mesh_terms: D000818:Animals; D001119:Arginase / Q000235:genetics / Q000378:metabolism*; D016923:Cell Death; D002470:Cell Survival; D017353:Gene Deletion; D008810:Mice, Inbred C57BL; D055806:Microvessels / Q000473:pathology; D008954:Models, Biological; D009410:Nerve Degeneration / Q000201:enzymology* / Q000473:pathology*; D009457:Neuroglia / Q000473:pathology; D009474:Neurons / Q000201:enzymology / Q000473:pathology; D000066829:Neuroprotection; D018384:Oxidative Stress; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015427:Reperfusion Injury / Q000201:enzymology* / Q000473:pathology; D012171:Retinal Vessels / Q000201:enzymology* / Q000473:pathology*
chemical_list: D012333:RNA, Messenger; D001119:Arginase