Sarah Hayton

Soluble Guanylate Cyclase α1–Deficient Mice: A Novel Murine Model for Primary Open Angle Glaucoma

Primary open angle glaucoma (POAG) is a leading cause of blindness worldwide. The molecular signaling involved in the pathogenesis of POAG remains unknown. Here, we report that mice lacking the α1 subunit of the nitric oxide receptor soluble guanylate cyclase represent a novel and translatable animal model of POAG, characterized by thinning of the retinal nerve fiber layer and loss of optic nerve axons in the context of an open iridocorneal angle. The optic neuropathy associated with soluble guanylate cyclase α1–deficiency was accompanied by modestly increased intraocular pressure and retinal vascular dysfunction. Moreover, data from a candidate gene association study suggests that a variant in the locus containing the genes encoding for the α1 and β1 subunits of soluble guanylate cyclase is associated with POAG in patients presenting with initial paracentral vision loss, a disease subtype thought to be associated with vascular dysregulation. These findings provide new insights into the pathogenesis and genetics of POAG and suggest new therapeutic strategies for POAG.

Genetic modifiers of hypertension in soluble guanylate cyclase α1–deficient mice

Nitric oxide (NO) plays an essential role in regulating hypertension and blood flow by inducing relaxation of vascular smooth muscle. Male mice deficient in a NO receptor component, the α1 subunit of soluble guanylate cyclase (sGCα1), are prone to hypertension in some, but not all, mouse strains, suggesting that additional genetic factors contribute to the onset of hypertension. Using linkage analyses, we discovered a quantitative trait locus (QTL) on chromosome 1 that was linked to mean arterial pressure (MAP) in the context of sGCα1 deficiency. This region is syntenic with previously identified blood pressure-related QTLs in the human and rat genome and contains the genes coding for renin. Hypertension was associated with increased activity of the renin-angiotensin-aldosterone system (RAAS). Further, we found that RAAS inhibition normalized MAP and improved endothelium-dependent vasorelaxation in sGCα1-deficient mice. These data identify the RAAS as a blood pressure-modifying mechanism in a setting of impaired NO/cGMP signaling.

Soluble guanylate cyclase-α1 is required for the cardioprotective effects of inhaled nitric oxide.

Reperfusion injury limits the benefits of revascularization in the treatment of myocardial infarction (MI). Breathing nitric oxide (NO) reduces cardiac ischemia-reperfusion injury in animal models; however, the signaling pathways by which inhaled NO confers cardioprotection remain uncertain. The objective of this study was to learn whether inhaled NO reduces cardiac ischemia-reperfusion injury by activating the cGMP-generating enzyme, soluble guanylate cyclase (sGC), and to investigate whether bone marrow (BM)-derived cells participate in the sGC-mediated cardioprotective effects of inhaled NO. Wild-type (WT) mice and mice deficient in the sGC α(1)-subunit (sGCα(1)(-/-) mice) were subjected to cardiac ischemia for 1 h, followed by 24 h of reperfusion. During ischemia and for the first 10 min of reperfusion, mice were ventilated with oxygen or with oxygen supplemented with NO (80 parts per million). The ratio of MI size to area at risk (MI/AAR) did not differ in WT and sGCα(1)(-/-) mice that did not breathe NO. Breathing NO decreased MI/AAR in WT mice (41%, P = 0.002) but not in sGCα(1)(-/-) mice (7%, P = not significant). BM transplantation was performed to restore WT BM-derived cells to sGCα(1)(-/-) mice. Breathing NO decreased MI/AAR in sGCα(1)(-/-) mice carrying WT BM (39%, P = 0.031). In conclusion, these results demonstrate that a global deficiency of sGCα(1) does not alter the degree of cardiac ischemia-reperfusion injury in mice. The cardioprotective effects of inhaled NO require the presence of sGCα(1). Moreover, our studies suggest that BM-derived cells are key mediators of the ability of NO to reduce cardiac ischemia-reperfusion injury.

Genetic mapping of a modifier locus affecting hypertension in soluble guanylate cyclase α1 deficient mice

Background We previously reported that male mice deficient in the a1 subunit of the NO receptor soluble guanylate cyclase (sGCa1 -/mice), an important nitric oxide (NO) receptor, are hypertensive [1]. The phenotype depends on the genetic background: sGCa1 -/mice on a 129S6 (S6) background (sGCa1 ) but not on a C57BL/6 (B6) background (sGCa1 ) develop hypertension [2]. These findings suggest that hypertension associated with sGCa1-deficiency is modulated by genetic factors. We aimed to identify modifier genes underlying the hypertension in sGCa1 -/-S6 mice.

sGCα1-deficient mice: a novel murine model of spontaneous primary open angle glaucoma

Background Primary open angle glaucoma (POAG) is a progressive eye disease that leads to blindness due to the irreversible loss of retinal ganglion cells and degeneration of the optic nerve (ON). As of yet, there is no cure for glaucoma. Although available therapies delay disease progression, they offer incomplete protection. Elevated intraocular pressure (IOP) is an important risk factor for POAG. However, the exact molecular mechanisms that trigger increased IOP and glaucomatous optic neuropathy remain incompletely understood. While a few spontaneous murine models of glaucoma exist, none are models of POAG, the most prevalent form of glaucoma. Impaired nitric oxide (NO) signaling has been implicated in the development of glaucoma. To further test the hypothesis that impaired NO/cGMP signaling contributes to the pathogenesis of POAG, we tested whether mice lacking the a1 subunit of the NO receptor soluble guanylate cyclase (sGCa1 -/mice) develop POAG.