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 $α_1$ 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 $α_1$–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 $α_1$ and $β_1$ 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

Atrial natriuretic peptide is negatively regulated by microRNA-425

Numerous common genetic variants have been linked to blood pressure, but no underlying mechanism has been elucidated. Population studies have revealed that the variant rs5068 (A/G) in the 3′ untranslated region of NPPA, the gene encoding atrial natriuretic peptide (ANP), is associated with blood pressure. We selected individuals on the basis of rs5068 genotype (AG vs. AA) and fed them a low- or high-salt diet for 1 week, after which they were challenged with an intravenous saline infusion. On both diets, before and after saline administration, ANP levels were up to 50% higher in AG individuals than in AA individuals, a difference comparable to the changes induced by high-salt diet or saline infusion. In contrast, B-type natriuretic peptide levels did not differ by rs5068 genotype. We identified a microRNA, miR-425, that is expressed in human atria and ventricles and is predicted to bind the sequence spanning rs5068 for the A, but not the G, allele. miR-425 silenced NPPA mRNA in an allele-specific manner, with the G allele conferring resistance to miR-425. This study identifies miR-425 as a regulator of ANP production, raising the possibility that miR-425 antagonists could be used to treat disorders of salt overload, including hypertension and heart failure

Engineered, Stem Cell-Derived Retinal Tissue For Treating Macular Degeneration In A Porcine Model

Cell replacement therapy with induced pluripotent stem cells (iPSCs) is a promising treatment for diseases of retinal degeneration such as Age Related Macular Degeneration (AMD). Despite progress in the ability to derive retinal progenitor cells from pluripotent cell in vitro, the ability to engineer a transplantable retinal tissue remains a challenge and the necessary large animal models in which to study implantation are lacking. In this study we established the biocompatibility of iPSC derived retinal progenitor cells (RPCs) and human fetal retinal pigment epithelium (hfRPE) with a novel scaffold composed of gelatin, chondroitin sulfate, and hyaluronic acid (GCH). iPSC-RPCs seeded onto GCH scaffolds either as clusters or after dissociation into single cells attached to, proliferated, and differentiated towards a neural retinal fate as evidenced by gene expression and immunohistochemistry. Dissociation of RPC clusters before seeding, however, resulted in a significant decrease in expression of Recoverin, a key photoreceptor marker. This study also established a model of outer retinal damage in pigs. Argon laser induced outer retinal damage in the porcine visual streak and was detected on histology and multifocal electroretinography (mfERG) at time points immediately after and 10 days after injury. This study laid the groundwork for a pilot study of subretinal GCH scaffold implantation in pigs

Never Too Young or Too Old

An 81-year-old woman with history of ocular myasthenia gravis presented with sequential bilateral vision loss. Six days before presentation, she discovered that vision of her left eye was reduced to light perception. She did not have any eye pain, pain with eye movement, headache, scalp tenderness, jaw claudication, muscle soreness, rash, or joint aches. An ophthalmologist, documented no light perception vision with an afferent pupillary defect on the left, and a normal visual acuity on the right but visual field testing demonstrated a dense hemifield defect in the right eye. Dilated funduscopic exam was normal. A non-contrast brain MRI was reported as normal. CTA Head and Neck showed moderate to severe stenosis of one of the vertebral arteries. Erythrocyte sedimentation rate was 55 but due to absence of symptoms suggestive of temporal arteritis, she was not started on steroids but instead diagnosed with a stroke and treated with dual antiplatelet therapy. Four days later, the patient woke up with vision in the right eye severely diminished to the point of seeing only outlines and movement. The next day, vision worsened to bilateral no light perception. On examination, pupils were slightly reactive to light but there was a left afferent pupillary defect. The right and especially the left optic disc were felt to be slightly pale. IV steroids were started for suspected giant cell arteritis. An MRI brain and orbits with contrast revealed enlargement and enhancement of the bilateral proximal prechiasmatic optic nerves, optic chiasm, and proximal optic tracts with extension into the hypothalamus. MRI cervical and thoracic spine was normal. CSF was notable for no pleocytosis but a mildly elevated protein of 59 mg/dL, with negative CSF cytology and oligoclonal bands. Additional studies were obtained. Eight months later the patient died of an unrelated cause, and an autopsy was performed

Never Too Young or Too Old

An 81-year-old woman with history of ocular myasthenia gravis presented with sequential bilateral vision loss. Six days before presentation, she discovered that vision of her left eye was reduced to light perception. She did not have any eye pain, pain with eye movement, headache, scalp tenderness, jaw claudication, muscle soreness, rash, or joint aches. An ophthalmologist, documented no light perception vision with an afferent pupillary defect on the left, and a normal visual acuity on the right but visual field testing demonstrated a dense hemifield defect in the right eye. Dilated funduscopic exam was normal. A non-contrast brain MRI was reported as normal. CTA Head and Neck showed moderate to severe stenosis of one of the vertebral arteries. Erythrocyte sedimentation rate was 55 but due to absence of symptoms suggestive of temporal arteritis, she was not started on steroids but instead diagnosed with a stroke and treated with dual antiplatelet therapy. Four days later, the patient woke up with vision in the right eye severely diminished to the point of seeing only outlines and movement. The next day, vision worsened to bilateral no light perception. On examination, pupils were slightly reactive to light but there was a left afferent pupillary defect. The right and especially the left optic disc were felt to be slightly pale. IV steroids were started for suspected giant cell arteritis. An MRI brain and orbits with contrast revealed enlargement and enhancement of the bilateral proximal prechiasmatic optic nerves, optic chiasm, and proximal optic tracts with extension into the hypothalamus. MRI cervical and thoracic spine was normal. CSF was notable for no pleocytosis but a mildly elevated protein of 59 mg/dL, with negative CSF cytology and oligoclonal bands. Additional studies were obtained. Eight months later the patient died of an unrelated cause, and an autopsy was performed

Never Too Young or Too Old

An 81-year-old woman with history of ocular myasthenia gravis presented with sequential bilateral vision loss. Six days before presentation, she discovered that vision of her left eye was reduced to light perception. She did not have any eye pain, pain with eye movement, headache, scalp tenderness, jaw claudication, muscle soreness, rash, or joint aches. An ophthalmologist, documented no light perception vision with an afferent pupillary defect on the left, and a normal visual acuity on the right but visual field testing demonstrated a dense hemifield defect in the right eye. Dilated funduscopic exam was normal. A non-contrast brain MRI was reported as normal. CTA Head and Neck showed moderate to severe stenosis of one of the vertebral arteries. Erythrocyte sedimentation rate was 55 but due to absence of symptoms suggestive of temporal arteritis, she was not started on steroids but instead diagnosed with a stroke and treated with dual antiplatelet therapy. Four days later, the patient woke up with vision in the right eye severely diminished to the point of seeing only outlines and movement. The next day, vision worsened to bilateral no light perception. On examination, pupils were slightly reactive to light but there was a left afferent pupillary defect. The right and especially the left optic disc were felt to be slightly pale. IV steroids were started for suspected giant cell arteritis. An MRI brain and orbits with contrast revealed enlargement and enhancement of the bilateral proximal prechiasmatic optic nerves, optic chiasm, and proximal optic tracts with extension into the hypothalamus. MRI cervical and thoracic spine was normal. CSF was notable for no pleocytosis but a mildly elevated protein of 59 mg/dL, with negative CSF cytology and oligoclonal bands. Additional studies were obtained. Eight months later the patient died of an unrelated cause, and an autopsy was performed