Preserve the (intraocular) environment: the importance of maintaining normal oxygen gradients in the eye

Beebe, David C.; Shui, Ying Bo; Siegfried, Carla J.; Holekamp, Nancy M.; Bai, Fang

doi:10.1007/s10384-014-0318-4

Cited by 71 publications

(68 citation statements)

References 29 publications

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“…Thus, understanding the processes that control oxygen transport, concentration, and distribution in the lens are very important. Oxygen consumption is necessary to maintain a low oxygen concentration inside the eye lens; otherwise the concentration of oxygen would be equal to that outside the lens (Beebe et al, 2014; Siegfried et al, 2010). Mitochondrial respiration occurring in the outer layers of cortical fiber cells (not yet mature and containing organelles, including mitochondria) accounts for approximately 90% of oxygen consumption by the lens (McNulty et al, 2004), ensuring a low oxygen concentration in the lens nucleus.…”

Section: Discussionmentioning

confidence: 99%

Lipid domains in intact fiber-cell plasma membranes isolated from cortical and nuclear regions of human eye lenses of donors from different age groups

Raguž

Mainali

O’Brien

et al. 2015

Experimental Eye Research

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The results reported here clearly document changes in the properties and the organization of fiber-cell membrane lipids that occur with age, based on electron paramagnetic resonance (EPR) analysis of lens membranes of clear lenses from donors of age groups from 0 to 20, 21 to 40, and 61 to 80 years. The physical properties, including profiles of the alkyl chain order, fluidity, hydrophobicity, and oxygen transport parameter, were investigated using EPR spin-labeling methods, which also provide an opportunity to discriminate coexisting lipid domains and to evaluate the relative amounts of lipids in these domains. Fiber-cell membranes were found to contain three distinct lipid environments: bulk lipid domain, which appears minimally affected by membrane proteins, and two domains that appear due to the presence of membrane proteins, namely boundary and trapped lipid domains. In nuclear membranes the amount of boundary and trapped phospholipids as well as the amount of cholesterol in trapped lipid domains increased with the donors’ age and was greater than that in cortical membranes. The difference between the amounts of lipids in domains uniquely formed due to the presence of membrane proteins in nuclear and cortical membranes increased with the donors’ age. It was also shown that cholesterol was to a large degree excluded from trapped lipid domains in cortical membranes. It is evident that the rigidity of nuclear membranes was greater than that of cortical membranes for all age groups. The amount of lipids in domains of low oxygen permeability, mainly in trapped lipid domains, were greater in nuclear than cortical membranes and increased with the age of donors. These results indicate that the nuclear fiber cell plasma membranes were less permeable to oxygen than cortical membranes and become less permeable to oxygen with age. In clear lenses, age-related changes in the lens lipid and protein composition and organization appear to occur in ways that increase fiber cell plasma membrane resistance to oxygen permeation.

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Section: Discussionmentioning

confidence: 99%

Lipid domains in intact fiber-cell plasma membranes isolated from cortical and nuclear regions of human eye lenses of donors from different age groups

Raguž

Mainali

O’Brien

et al. 2015

Experimental Eye Research

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“…Several groups have shown that vitrectomy and cataract surgery significantly increase IOP and the risk of developing POAG, 55,56 which is due to exposure of the TM and SC to a higher level of oxygen causing oxidative damage to these tissues. 57,58 We demonstrated in vitro in an aging model of hyperoxia that it altered eNOS and its phosphorylation status and resulted in reduced NO production. Together with our previous data 39,49 showing that hyperoxia can cause increased resistance at the level of SC, these findings suggest that vitrectomy and phacoemulsification and the related oxygen concentration elevation could cause increased IOP by damaging SC.…”

Section: Discussionmentioning

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

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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...

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“…While one could argue that nothing new was to be expected concerning the protective role of GSH in the lens, our interest in GSH homeostasis in the lens was rekindled with the unexpected finding that lenticular GSH levels were not completely suppressed in the LEGSKO mouse in spite of complete absence of γ-glutamylcysteine ligase(Fan et al, 2012). This issue, which is the subject of intense investigation in our laboratory, is closely linked to lenticular ascorbate metabolism and cataractogenesis and the work of David Beebe who has pioneered the importance of the vitreous as a source of oxidative stress to the lens(Beebe et al, 2014; Holekamp et al, 2005; Li et al, 2013b; Shui et al, 2009). These paradigm shifting studies inspired us to study lens biology in connection not only to the aqueous humor but also to the vitreous humor.…”

Section: Introductionmentioning

confidence: 99%

Lens glutathione homeostasis: Discrepancies and gaps in knowledge standing in the way of novel therapeutic approaches

Fan

Monnier

Whitson

2017

Experimental Eye Research

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Cataract is the major cause of blindness worldwide. The WHO has estimated around 20 million people have bilateral blindness from cataract, and that number is expected to reach 50 million in 2050. The cataract surgery is currently the main treatment approach, though often associated with complications, such as Posterior Capsule Opacification (PCO)-also known as secondary cataract. The lens is an avascular ocular structure equipped with an unusually high level of glutathione (GSH), which plays a vital role in maintaining lens transparency by regulating lenticular redox state. The lens epithelium and outer cortex are thought to be responsible for providing the majority of lens GSH via GSH de novo synthesis, assisted by a continuous supply of constituent amino acids from the aqueous humor, as well as extracellular GSH recycling from the gamma-glutamyl cycle. However, when de novo synthesis is impaired, in the presence of low GSH levels, as in the aging human lens, compensatory mechanisms exist, suggesting that the lens is able to uptake GSH from the surrounding ocular tissues. However, these uptake mechanisms, and the GSH source and its origin, are largely unknown. The lens nucleus does not have the ability to synthesize its own GSH and fully relies on transport from the outer cortex by yet unknown mechanisms. Understanding how aging reduces GSH levels, particularly in the lens nucleus, how it is associated with age-related nuclear cataract (ARNC), and how the lens compensates for GSH loss via external uptake should be a major research priority. The intent of this review, which is dedicated to the memory of David C. Beebe, is to summarize our current understanding of lens GSH homeostasis and highlight discrepancies and gaps in knowledge that stand in the way of pharmacologically minimizing the impact of declining GSH content in the prevention of age-related cataract.

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Preserve the (intraocular) environment: the importance of maintaining normal oxygen gradients in the eye

Cited by 71 publications

References 29 publications

Lipid domains in intact fiber-cell plasma membranes isolated from cortical and nuclear regions of human eye lenses of donors from different age groups

Lipid domains in intact fiber-cell plasma membranes isolated from cortical and nuclear regions of human eye lenses of donors from different age groups

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

Lens glutathione homeostasis: Discrepancies and gaps in knowledge standing in the way of novel therapeutic approaches

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