Inducible nitric oxide synthase-mediated alteration of mitochondrial OPA1 expression in ocular hypertensive rats.

PURPOSE: To investigate how OPA1 expression and distribution are altered by increased nitric oxide (NO) and whether aminoguanidine, a relative selective NO synthase (NOS)-2 inhibitor, can restore OPA1 expression and subsequently increase retinal ganglion cell (RGC) survival in ocular hypertensive rats.
METHODS: Elevated intraocular pressure was induced unilaterally by translimbal laser photocoagulation of the trabecular meshwork in Sprague-Dawley rats. Aminoguanidine (100 mg/kg) was administered by intraperitoneal injection for 3 consecutive days in rats after laser treatment. Preservation of fluorochrome-labeled RGCs was assessed 2 weeks later. GFAP, NOS-2, or OPA1 protein expression and distribution were assessed by Western blot analysis and immunohistochemistry. OPA1 mRNA was measured by qPCR.
RESULTS: OPA1 mRNA and protein expression were significantly increased in the vehicle-treated hypertensive rat retina. Aminoguanidine treatment significantly reduced expression of the 90- and 65-kDa OPA1 isoforms but did not significantly change the 80-kDa OPA1 isoform in hypertensive retina. In addition, the increases in NOS-2 and GFAP protein expression were blocked by aminoguanidine treatment in the hypertensive retina. NOS-2 immunoreactivity was induced in cells of the ganglion cell layer in the vehicle-treated hypertensive retina. Aminoguanidine treatment significantly increased RGC survival at 2 weeks after IOP elevation.
CONCLUSIONS: Although NOS-2/NO induction may contribute to hypertensive retinal cell death, an increase in mitochondrial OPA1 may provide an important cellular defense mechanism against pressure-mediated retinal damage. These findings suggest that mitochondrial preservation after inhibition of NOS-2 may be useful for protecting RGCs against glaucomatous damage.