Open Angle Glaucoma In Soluble Guanylate Cyclase α1-deficient Mice And Its Association With The Gucy1a3/gucy1b3 Locus In Humans

Abstract

Purpose: : Primary open angle glaucoma (POAG) is a leading cause of blindness, due to irreversible retinal ganglion cell (RGC) loss. Currently, there is no cure for POAG and available therapies offer incomplete protection, highlighting the need for novel drug targets. Impaired nitric oxide (NO) signaling, well known to contribute to systemic vascular dysfunction, has been implicated in the development of POAG. This project aimed to evaluate the NO receptor soluble guanylate cyclase (sGC), a heterodimeric cGMP-generating enzyme consisting of an α and a β subunit, as a potential therapeutic target for elevated IOP and POAG.

Methods: : IOP was measured using a TonoLab-tonometer in female wild type (WT) mice and in female mice deficient in the α1 subunit of sGC (sGCα1-/- mice). The rate of aqueous humor (AqH) outflow was quantified via fluorophotometry. Retinal nerve fiber layer (RNFL) thickness was assessed using spectral-domain optical coherence tomography, and optic nerve axons were stained with paraphenylenediamine and counted. 51 single nucleotide polymorphisms (SNPs), located throughout the genomic region that includes GUCY1A3 and GUCY1B3 (encoding the sGCα1 and sGCβ1 subunits, respectively), were genotyped in 788 women (106 cases and 682 controls, a sub-set from the Glaucoma Genes and Environment (GLAUGEN) study) for their association with a subtype of POAG with incident paracentral scotomas.

Results: : An age-dependent increase in IOP, decrease in AqH outflow rate, thinning of the RNFL, and optic neuropathy were observed in sGCα1-/- mice but not in WT mice. In the targeted association study in woman, rs11722059, a SNP located in the GUCY1A3/GUCY1B3 intergenic region, was significantly associated with POAG characterized by paracentral visual field loss (OR=1.9 [95% CI:1.34-2.69]; P=3.2x10-4).

Conclusions: : NO-cGMP signaling modulates IOP and AqH outflow, and impairing NO-cGMP signaling results in optic neuropathy in mice. These findings identify sGCα1-/- mice as a new animal model for POAG, providing a unique opportunity to study the mechanisms underlying POAG pathogenesis and to test new strategies for disease prevention. Also, the relevance of sGC as a potential therapeutic target in POAG is highlighted by the association of the GUCY1A3/GUCY1B3 locus with glaucomatous paracentral vision loss in women. These results identify a role for sGCα1 in a POAG phenotype thought to be associated with vascular dysregulation.

Keywords: genetics • nitric oxide • pathology: experimental