Retinal Ganglion Cell Apoptosis in Glaucoma Is Related to Intraocular Pressure and IOP-Induced Effects on Extracellular Matrix

Guo, Li; Moss, Stephen E.; Alexander, Robert; Ali, Robin R.; Fitzke, F.W.; Cordeiro, M. Francesca

doi:10.1167/iovs.04-0832

Cited by 308 publications

(280 citation statements)

References 37 publications

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“…The correlation between the level of RGC apoptosis and MMP-9 activity suggests the existence of a mechanism mediating glaucomatous RGC loss via MMP-9 [14]. In agreement with this data are results showing that the inhibition of MMP-9 reduces RGC apoptosis and tissue remodeling [15].…”

Section: Introductionsupporting

confidence: 68%

“…MMP-9 is secreted in the body in a latent form and upon activation acts on many inflammatory substrates, contributing to the progression of many human disorders, including glaucoma and other retinal disorders [14,30,31]. In the earlier studies regulation of MMP-9 protein levels has been largely ascribed to transcriptional activation of the gene [32].…”

Section: Discussionmentioning

confidence: 99%

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Matrix metalloproteinase 9 expression: new regulatory elements

Surgucheva

Chidambaram

Willoughby

et al. 2010

j ocul biol dis inform

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Retinal ganglion cells apoptosis is linked to matrix metalloproteinase 9 (MMP-9) controlled changes of extracellular matrix. Abnormal expression of MMP-9 is associated with glaucomatous alterations. Thus, the knowledge of MMP-9 regulation is important for the understanding the pathogenesis of glaucoma. Here, we investigated the role of 3′-untranslated regions (3′-UTR) and microRNAs in MMP-9 regulation. We used in vitro mutagenesis and Luc reporter system to identify regulatory elements in the 3′-UTR of MMP-9. microRNAs were analyzed by qRT-PCR, and their role was investigated with inhibitors and mimics. We identified targets for miRNAs in 3′-UTR of MMP-9 involved in the regulation of MMP-9 expression. We then isolated miRNAs from the optic nerve A7 astrocytes and 293 T cells and confirmed the role of mi340 in the regulation using specific inhibitors and mimics. The results obtained show a new miRNA-mediated mechanism of MMP-9 expression regulation.

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Section: Introductionsupporting

confidence: 68%

Section: Discussionmentioning

confidence: 99%

Matrix metalloproteinase 9 expression: new regulatory elements

Surgucheva

Chidambaram

Willoughby

et al. 2010

j ocul biol dis inform

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“…This strategy has been used to identify apoptotic RGCs in vivo (10,(14)(15)(16). One potential drawback to this strategy is that it may not adequately distinguish apoptotic from necrotic forms of cell death in vivo without a secondary marker of membrane integrity.…”

mentioning

confidence: 99%

Single-cell imaging of retinal ganglion cell apoptosis with a cell-penetrating, activatable peptide probe in an in vivo glaucoma model

Barnett

Zhang

Maxwell

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

125

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Molecular imaging probes have potential for in vivo identification of apoptosis and other intracellular processes. TcapQ, a cell-penetrating, near-infrared fluorescent peptide probe designed to be optically silent through intramolecular fluorescence quenching and activated by effector caspases, has been previously described and validated in vitro. Herein, using NMDA-induced apoptosis of retinal ganglion cells (RGCs), representing an in vivo rat model of glaucoma, we assessed the ability of TcapQ to image single-cell apoptosis through effector caspase activity. Following intravitreal injection, intracellular TcapQ activation occurred specifically in RGCs, identified individual apoptotic cells, showed a clear dose-response relationship with NMDA, and colocalized with TUNEL labeling in the retina. There was a significant diminution of probe activation following pretreatment with a specific inhibitor of caspase-3. Stereospecificity was also exhibited by the lack of intracellular fluorescence upon administration of the noncleavable isomer, d TcapQ. TcapQ has potential utility in detecting and monitoring single-cell apoptosis in glaucoma in vivo.

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“…Retinal matrix metalloproteinase activity has been related to RGC death including that induced by IOP elevation (Guo et al, 2005). Although direct pathogenic role of matrix metalloproteinases in glaucoma is unclear, these proteases have been suggested to play a role in glutamate receptor processing thereby predisposing RGCs to damage.…”

Section: Interplay Of Tnf-α Signaling With Other Cellular Events Assomentioning

confidence: 99%

TNF-α signaling in glaucomatous neurodegeneration

Tezel

2008

Progress in Brain Research

232

190

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Growing evidence supports the role of TNF-α as a mediator of neurodegeneration in glaucoma. Glial production of TNF-α is increased and its death receptor is up-regulated on retinal ganglion cells (RGCs) and optic nerve axons in glaucomatous eyes. This multifunctional cytokine can induce RGC death through receptor-mediated caspase activation, mitochondrial dysfunction, and oxidative stress. Opposing these cell-death promoting signals, binding of TNF receptors can also trigger the activation of survival signals. A critical balance between a variety of intracellular signaling pathways determines the predominant in vivo bioactivity of TNF-α as best exemplified by differential responses of RGCs and glia. In addition to the direct neurotoxicity of TNF-α to RGCs and their axons, potential interplay of TNF-α signaling with other cellular events associated with glaucomatous neurodegeneration may also contribute to secondary neurodegenerative injury. This review focuses on the present evidence supporting the involvement of TNF-α signaling in glaucomatous neurodegeneration and possible treatment targets to provide neuroprotection.

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Retinal Ganglion Cell Apoptosis in Glaucoma Is Related to Intraocular Pressure and IOP-Induced Effects on Extracellular Matrix

Cited by 308 publications

References 37 publications

Matrix metalloproteinase 9 expression: new regulatory elements

Matrix metalloproteinase 9 expression: new regulatory elements

Single-cell imaging of retinal ganglion cell apoptosis with a cell-penetrating, activatable peptide probe in an in vivo glaucoma model

TNF-α signaling in glaucomatous neurodegeneration

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