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Yi Dai, Robert Weinreb, Xinghuai Sun, James D. Lindsey, Won-Kyu Ju; Inducible Nitric Oxide Synthase-Mediated Alteration of Mitochondrial OPA1 Expression in Ocular Hypertensive Rats. Invest. Ophthalmol. Vis. Sci. 2011;52(14):5327.
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To investigate how OPA1 expression and distribution is altered by increased nitric oxide (NO), and whether aminoguanidine, a relative selective NO synthase-2 (NOS-2) inhibitor, can restore OPA1 expression and subsequently increase retinal ganglion cell (RGC) survival in ocular hypertensive rats.
Elevated intraocular pressure was induced unilaterally by translimbal laser photocoagulation of the trabecular meshwork in Sprague-Dawley rats. Aminoguanidine (100mg/kg) was administered by intraperitoneal injection for 3 consecutive days in rats following laser treatment. Preservation of FluoroGold-labeled RGCs was assessed 2 weeks later. GFAP, NOS-2 or OPA1 protein expression and distribution were assessed by Western blot and immunohistochemistry. OPA1 mRNA was measured by qPCR.
OPA1 mRNA and protein expression were significantly increased in vehicle-treated hypertensive rat retina. Aminoguanidine treatment significantly reduced the expression of the 90- and 65-kDa OPA1 isoforms, but did not significantly change the 80-kDa OPA1 isoform in hypertensive retina. Also, the increase of NOS-2 and GFAP protein expression were blocked by aminoguanidine treatment in hypertensive retina. NOS-2 immunoreactivity was induced in cells of the ganglion cell layer in vehicle-treated hypertensive retina. Aminoguanidine treatment significantly increased RGC survival at 2 weeks following IOP elevation.
While NOS-2/NO induction may contribute to hypertensive retinal cell death, mitochondrial OPA1 increase may provide an important cellular defense mechanism against pressure-mediated retinal damage. These findings suggest that mitochondrial preservation following inhibition of NOS-2 may be useful for protecting RGCs against glaucomatous damage.
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