June 2015
Volume 56, Issue 7
Free
ARVO Annual Meeting Abstract  |   June 2015
Mechanisms of Neurovascular protection in Retinal Ischemia Reperfusion Injury: Role of Arginase
Author Affiliations & Notes
  • Esraa Shosha
    Vascular Biology Center, Georgia Regents University, Augusta, GA
    Vision Discovery Institute, Georgia Regents University, Augusta, GA
  • Zhimin Xu
    Vascular Biology Center, Georgia Regents University, Augusta, GA
    Vision Discovery Institute, Georgia Regents University, Augusta, GA
  • Tahira Lemtalsi
    Vascular Biology Center, Georgia Regents University, Augusta, GA
    Vision Discovery Institute, Georgia Regents University, Augusta, GA
  • S Priya Narayanan
    College of Allied Health Sciences, Georgia Regents University, Augusta, GA
    Vision Discovery Institute, Georgia Regents University, Augusta, GA
  • Ruth B Caldwell
    Vascular Biology Center, Georgia Regents University, Augusta, GA
    Vision Discovery Institute, Georgia Regents University, Augusta, GA
  • Footnotes
    Commercial Relationships Esraa Shosha, None; Zhimin Xu, None; Tahira Lemtalsi, None; S Narayanan, None; Ruth Caldwell, None
  • Footnotes
    Support None
Investigative Ophthalmology & Visual Science June 2015, Vol.56, 14. doi:
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      Esraa Shosha, Zhimin Xu, Tahira Lemtalsi, S Priya Narayanan, Ruth B Caldwell; Mechanisms of Neurovascular protection in Retinal Ischemia Reperfusion Injury: Role of Arginase. Invest. Ophthalmol. Vis. Sci. 2015;56(7 ):14.

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

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Abstract

Purpose: Ischemia reperfusion (I/R) injury occurs upon restoration of tissue blood supply after a period of ischemia. It is cardinal in many retinal diseases such as retinal vein occlusion, diabetic retinopathy and retinopathy of prematurity. Although there has been much emphasis on studying protective measures that can prevent or reverse I/R insult, there is no clinically effective treatment mainly because the molecular mechanisms by which microvascular dysfunction and injury happens are far from clear.<br /> We have previously shown that deletion of arginase 2 (A2) prevented neuronal loss and retinal degeneration in I/R model (Xu et al ARVO 2014).The present study was undertaken to investigate the molecular mechanisms by which A2 function mediates neuro-vascular injury following by retinal I/R insult.

Methods: Studies were performed using Wild type (WT) mice (C57BL6J) and mice deficient in arginase 2 (A2-/-) or lacking one copy of arginase 1 (A1+/-). Ischemia reperfusion (I/R) insult was conducted on the right eye and left eye underwent sham surgery. In vitro model of I/R was performed using bovine retinal endothelial (BRE) cells subjected to oxygen glucose deprivation/reperfusion (OGD/R). Western blotting and RT-PCR were performed to study alterations in pro-inflammatory and pro-survival pathways. Microvascular and neurovascular degeneration were evaluated using vascular digests and NeuN staining, respectively. Microglial activation was evaluated using immunolabeling for Iba-1 and confocal imaging.

Results: Our studies showed that A2 levels were increased after I/R injury in both in vitro and in vivo models of I/R insult. Deletion of A2 significantly diminished I/R induced neuronal and microvascular degeneration in vivo. OGD/R induced endothelial cell death as shown by increases in cleaved PARP. I/R injury resulted in downregulation of prosurvival markers such as A1, SIRT-3, Bcl-xl and phosphorylated AKT and upregulation of proinflammatory markers like iNOS and p-NFkB. These changes were reversed with A2 deletion in vivo. Similarly, I/R induced microglial/ macrophage activation and neuronal cell loss were decreased with A2 deletion in vivo.

Conclusions: This study shows for the first time that I/R injury causes neurovascular degeneration through increased A2 expression. A2 deletion prevented this through activation of prosurvival signaling and downregulation of proinflammatory pathways.

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