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Zhimin Xu, Harumasa Yokota, Subhadra P. Narayanan, Robert W. Caldwell, Ruth B. Caldwell; Deletion of Arginase 2 Prevents Retinal Ganglion Cell Loss and Blocks Formation of Acellular Capillaries after Ischemia/Reperfusion Injury. Invest. Ophthalmol. Vis. Sci. 2012;53(14):5329.
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Excessive activity of the urea cycle enzyme arginase has been implicated in a variety of cardiovascular diseases. Our lab is investigating whether this enzyme could serve as a therapeutic target in ischemic retinopathy. Our previous studies have shown that deletion of arginase 2 (Arg2) significantly reduces retinal neuronal and vascular injury in a model of retinopathy of prematurity. In this study, we have evaluated the role of Arg2 in neuronal and capillary degeneration resulting from retinal ischemia/reperfusion (I/R) injury.
Wild type (C57BL/6) or Arg2 (-/-) mice were prepared in a model of I/R injury. I/R injury was produced by raising the intraocular pressure to 110 mmHg for 40 minutes followed by reperfusion for various times. The contralateral eye was used as sham control. NeuN staining and confocal imaging of whole mounted retinas was used to quantify neuronal cells in the ganglion cell layer (GCL) at 1 week after I/R. For this, 10 confocal images were randomly taken around the optic nerve at the ganglion cell layer in each retina. Then the ratio of the number of NeuN positive cells relative to that of the sham control eye was calculated. Formation of acellular capillaries was assessed by using trypsin digest procedures to isolate the retinal vasculature at 4 weeks after I/R.
I/R in the wild type mice resulted in a 60% reduction in the number of NeuN positive GCL neurons compared to the sham eyes (p<0.05). This neuronal cell loss was largely prevented in the Arg2-deficient mice which had a 40% increase in the number of NeuN positive GCL neurons compared to the WT I/R retinas (p<0.05). The formation of acellular capillaries was also significantly decreased in the Arg2-deficient mice. Whereas the number of acellular capillaries in the WT I/R retinas was increased by 8 fold above sham controls (p<0.001), the acellular capillaries in the Arg2-/- I/R retinas were increased by only 2 fold above the sham controls (p< 0.001).
Deletion of arginase 2 prevents the loss of GCL neurons and reduces the formation of acellular capillaries induced by I/R injury. These data suggest that inactivation of arginase 2 may offer a new strategy for preventing neuronal cell death as well as retinal vasculature damage in ischemic retinopathy.
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