April 2014
Volume 55, Issue 13
Free
ARVO Annual Meeting Abstract  |   April 2014
Arginase blockade preserves retinal neurons during ischemia/reperfusion injury
Author Affiliations & Notes
  • Zhimin Xu
    Vascular Biology Center, Georgia Regents University, Augusta, GA
  • Esraa Shosha
    Vascular Biology Center, Georgia Regents University, Augusta, GA
  • S. Priya Narayanan
    Vascular Biology Center, Georgia Regents University, Augusta, GA
  • Harumasa Yokota
    Ophthalmology, Asahikawa Medical University, Asahikawa, Japan
  • Robert William Caldwell
    Department of Pharmacology and Toxicology, Georgia Regents University, Augusta, GA
  • Ruth B Caldwell
    Vascular Biology Center, Georgia Regents University, Augusta, GA
    VA Medical Center, Augusta, GA
Investigative Ophthalmology & Visual Science April 2014, Vol.55, 1898. doi:
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      Zhimin Xu, Esraa Shosha, S. Priya Narayanan, Harumasa Yokota, Robert William Caldwell, Ruth B Caldwell; Arginase blockade preserves retinal neurons during ischemia/reperfusion injury. Invest. Ophthalmol. Vis. Sci. 2014;55(13):1898.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose: Our previous studies have shown that deletion of the urea/ornithine generating enzyme arginase 2 (A2) significantly reduces neuronal injury in a model of retinopathy of prematurity (Narayanan et al., 2011). To evaluate whether A2 could be a therapeutic target in other forms of ischemic retinopathy, we examined the role of A2 in neuronal death following retinal ischemia/reperfusion injury (I/R).

Methods: I/R injury was induced in the right eye of wild type (C57BL/6, WT) or A2-/- mice by raising the intraocular pressure to 110 mmHg for 40 minutes followed by reperfusion for different times. The left eye was used as sham control. Other WT mice were treated with the arginase inhibitor ABH (Amino-2-Borono-6-Hexanoic Acid, 10mg/kg/day, ip, 8 days). Whole mounted retinas were stained with NeuN antibody and neuronal cell loss in the ganglion cell layer (GCL) was quantified at 7 days after I/R. Thickness of the retina was evaluated by morphometric analysis of H&E stained retinal sections collected at 7 days after I/R injury. Western blotting was performed to examine the activation of stress pathways.

Results: There was a 40% reduction in the number of NeuN positive GCL neurons in the WT retinas exposed to I/R as compared to the WT sham controls (p<0.01). This neuronal cell loss was markedly attenuated in the A2-/- mice (p<0.05) and ABH-treated WT mice (p<0.01). The neuronal loss in the WT I/R retinas was accompanied by a significant thinning of the retina (10%, p<0.01). Retinal thinning was significantly inhibited in the A2-/- mice (4%, p<0.01) as compared to the WT. The neuronal cell protection in the A2-/- I/R retinas was associated with blockade of stress pathways as shown by ~50% decreases in phosphorylated JNK and p38MAPK as compared to the WT mice at 3 hours after I/R injury (p<0.05). Expression of receptor-interacting protein (RIP kinase 1), a regulator of necroptosis, was also reduced by 50% in A2-/- I/R retinas as compared to the WT retinas (p< 0.05).

Conclusions: Deletion of A2 or inhibition of arginase prevents the loss of GCL neurons and limits retinal thinning following I/R injury. Stress activated MAPK/JNK pathway and RIP-mediated necroptosis may be involved in the neuronal cell injury. These data demonstrate that A2 plays an important role in neuronal degeneration during I/R. Inactivation of A2 may offer a therapeutic strategy for preventing neuronal cell death in ischemic retinopathy.

Keywords: 572 ischemia • 615 neuroprotection • 426 apoptosis/cell death  
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