Nitric oxide proxies and ocular perfusion pressure in primary open angle glaucoma

“…19 The reduced NO in the plasma of POAG patients suggested that it might also alter ocular perfusion pressure, impacting retinal cells, including ganglion cells. 20 Nitric oxide appears to control outflow resistance. In human eyes, NOS reactivity was enriched in major sites of outflow resistance, including the TM and SC, as well as in collecting channels.…”

mentioning

confidence: 99%

Endothelial Nitric Oxide Synthase-Related Mechanotransduction Changes in Aged Porcine Angular Aqueous Plexus Cells

Lei

Stamer

et al. 2014

Investigative Ophthalmology & Visual Science

View full text Add to dashboard Cite

Citation: Lei Y, Stamer WD, Wu J, Sun X. Endothelial nitric oxide synthaserelated mechanotransduction changes in aged porcine angular aqueous plexus cells. Invest Ophthalmol Vis Sci. 2014;55:8402-8408. DOI: 10.1167/iovs.14-14992 PURPOSE. To investigate effects of aging on endothelial nitric oxide synthase (eNOS) expression and signaling in angular aqueous plexus (AAP) (functional equivalent to human Schlemm's canal) cells subjected to shear stress. METHODS.The AAP cells were isolated differentially from porcine outflow tissues using puromycin selection. Cell aging was induced by culturing cells in hyperoxia condition (40% oxygen and 5% carbon dioxide) for 14 days. The AAP cells grown in chamber slides were exposed to a shear stress of 8 dynes/cm 2 for 24 hours. Expression of eNOS, eNOS-phospho Thr495, eNOS-phospho Ser1177, and Akt-phospho was tested by Western blot analysis and immunofluorescence staining. Nitric oxide (NO) levels were measured using the Griess assay. RESULTS.Compared with control, eNOS levels in aged cells were significantly reduced by 60% (P < 0.05; n ¼ 6). Phosphorylation of eNOS at Ser1177 and Akt at Ser473 was 63% and 80% lower in aged cells, respectively, whereas phosphorylation of the eNOS inhibition site (Thr495) increased by 6.1-fold (P < 0.05; n ¼ 6). Shear stress (8 dynes/cm 2 for 24 hours) increased eNOS abundance (total protein and at cell borders) and phosphorylation at Ser1177 by 1.7-fold and 1.8-fold, respectively (P < 0.05; n ¼ 6), whereas aged cells were unresponsive. In control cells exposed to shear stress, the NO concentration was 1.8-fold higher than in the static group (P < 0.05; n ¼ 4); however, aged cells were unresponsive to shear stress (mean 6 SD, 4.3 6 1.3 vs. 4.1 6 1.4 lM).CONCLUSIONS. Aged AAP cells appear compromised in their mechanotransduction machinery involving eNOS, the protein product of the gene, NOS3, polymorphisms of which impart a risk for the development of glaucoma.Keywords: aging, Schlemm's canal, eNOS G laucoma comprises a group of complex and heterogeneous blinding diseases, affecting almost 60 million people worldwide. 1 Clinically, glaucoma is characterized by cupping of the optic nerve head and visual field loss. Elevated IOP is the primary risk factor for glaucomatous optic nerve damage, and reducing pressure remains the only treatable end point that slows or stops disease progression. The risk of developing POAG also clearly increases with age. 2-8 Primarily, IOP is determined by changes in aqueous humor outflow resistance, which is thought to reside mainly in the juxtacanalicular region, where the trabecular meshwork (TM) and the inner wall of Schlemm's canal (SC) cells interact. 9,10 The endothelial cells of the inner wall of SC are important in regulating outflow resistance and thus IOP. 11,12Nitric oxide (NO) regulation appears to have a role in POAG. Family association studies [13][14][15] show a relationship between NOS3 gene polymorphisms, which encode for endothelial NO synthase (eNOS), and POAG. These recent findings are consistent wit...

show abstract

“…Aqueous humor levels of NO/cGMP have known to be reduced in glaucomatous patients compared to nonglaucomatous patients. 21,22 Therefore, it is interesting to speculate whether a reduction in endogenous NO results in elevated IOP in addition to increased oxidative stress in the glaucomatous anterior segment, which would also likely abrogate sGCmediated relaxation of the outflow pathway. More studies are needed to prove these hypotheses.…”

Section: Discussionmentioning

confidence: 99%

“…It is suggested that the glaucomatous outflow pathway experiences extensive oxidative stress, which can result in its functional impairment leading up to elevated IOP. [22][23][24][25][26][27] Selective activation of the oxidized form of sGC should target mainly the diseased state of sGC in these putative target tissues, thus offering a highly innovative therapy for glaucoma that should work adjunctively with current therapies.In this manuscript, we describe some of the key preclinical attributes of MGV354, a novel sGC activator, that generates cGMP production in normal human trabecular meshwork (NTM) cells under oxidizing conditions and causes sustained IOP lowering when dosed once-daily topically in laser trabeculoplasty-induced ocular hypertensive cynomolgus monkeys. …”

mentioning

confidence: 99%

A Novel Selective Soluble Guanylate Cyclase Activator, MGV354, Lowers Intraocular Pressure in Preclinical Models, Following Topical Ocular Dosing

Prasanna

Ferrara

Adams

et al. 2018

Invest. Ophthalmol. Vis. Sci.

View full text Add to dashboard Cite

PURPOSE. The nitric oxide/soluble guanylate cyclase/protein kinase G (NO/sGC/PKG) is known to be involved in the regulation of intraocular pressure (IOP) and may be dysregulated in glaucoma. The purpose is to demonstrate that the sGC activator MGV354 lowers IOP in a monkey model of glaucoma and could be considered as a possible new clinical drug candidate. METHODS.Changes to cGMP were assessed in primary human trabecular meshwork (hNTM) cells and binding studies were conducted using human sGC full-length protein. Ocular safety tolerability, exposure, and efficacy studies were conducted in rabbit and monkey models following topical ocular dosing of MGV354.RESULTS. sGC was highly expressed in the human and cynomolgus monkey outflow pathways. MGV354 had a 7-fold greater Bmax to oxidized sGC compared to that of reduced sGC and generated an 8-to 10-fold greater cGMP compared to that of a reduced condition in hTM cells. A single topical ocular dose with MGV354 caused a significant dose-dependent reduction of 20% to 40% (versus vehicle), lasting up to 6 hours in pigmented rabbits and 24 hours postdose in a cynomolgus monkey model of glaucoma. The MGV354-induced IOP lowering was sustained up to 7 days following once-daily dosing in a monkey model of glaucoma and was greater in magnitude compared to Travatan (travoprost)-induced IOP reduction. Mild to moderate ocular hyperemia was the main adverse effect noted.CONCLUSIONS. MGV354 represents a novel class of sGC activators that can lower IOP in preclinical models of glaucoma. The potential for sGC activators to be used as effective IOPlowering drugs in glaucoma patients could be further determined in clinical studies.Keywords: soluble guanylate cyclase, monkey model of glaucoma, IOP, ODQ, cGMP, glaucoma T he estimated number of glaucoma cases globally is over 60 million, and primary open angle glaucoma accounts for >70% of the total cases. In the United States alone, over 120,000 patients are blind from this disease, accounting for 9% to 12% of all cases of blindness.1 Lowering of intraocular pressure (IOP) is the current gold standard for reducing visual field (VF) loss in glaucoma. However, up to 45% of patients who achieved an IOP-lowering target of 25% to 30% (6 to 8 mm Hg) from baseline IOP by medical treatment continued to show progressive VF loss. Every 1 mm Hg higher mean IOP in the follow-up period was associated with 13% higher risk of progressive VF loss for the study population, whereas each mm Hg reduction was associated with a 10% reduction in disease progression. Rhopressa and latanoprost, which lowered IOP by 1 to 3 mm Hg greater than the monotherapy comparators over 3 months of dosing in patients with glaucoma.5 IOP lowering via the NO/ cGMP signaling pathway is also well known. This is a key pathway in several physiologic processes, including platelet inhibition, smooth muscle relaxation, and neurotransmission. NO is the endogenous ligand of soluble guanylate cyclase (sGC). Binding of NO to the heme domain of sGC results in sGC activation and production ...

show abstract

Nitric oxide proxies and ocular perfusion pressure in primary open angle glaucoma

Cited by 123 publications

References 23 publications

Timolol Modulates Erythrocyte Nitric Oxide Bioavailability

Timolol Modulates Erythrocyte Nitric Oxide Bioavailability

Endothelial Nitric Oxide Synthase-Related Mechanotransduction Changes in Aged Porcine Angular Aqueous Plexus Cells

A Novel Selective Soluble Guanylate Cyclase Activator, MGV354, Lowers Intraocular Pressure in Preclinical Models, Following Topical Ocular Dosing

Contact Info

Product

Resources

About