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Xiangjun Yang, Jian Cai, David W Powell, Harsha Paladugu, Markus H Kuehn, Gulgun Tezel; Up-regulation of sirtuins in the glaucomatous human retina. Invest. Ophthalmol. Vis. Sci. 2014;55(13):2398.
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© ARVO (1962-2015); The Authors (2016-present)
Sirtuins (silent information regulators) are highly conserved NAD(+)-dependent protein deacetylases exerting beneficial effects against aging and age-related diseases. The sirtuin family members (SIRT1-7) that exhibit differences in tissue distribution, subcellular localization, enzymatic activity, and targets are activated by a variety of stressors, target the transcriptional regulators controlling the adaptive responses (such as p53, NF-κB, HSF1, FOXOs, PGC-1α, HIF-1α, STAT3), and modulate the major biological pathways involved in stress response, protein homeostasis, and mitochondrial function. Sirtuin activation promotes survival of neurons, including RGCs, by deacetylation and subsequent inhibition of p53-mediated apopototic pathways and NF-κB-induced inflammatory processes. This study aimed to determine whether the retinal extent and cellular localization of sirtuin expression are altered in glaucoma.
Protein expression was analyzed in human retinal protein samples (isolated from 10 glaucomatous and 10 non-glaucomatous donor eyes) by quantitative LC-MS/MS. To validate the proteomics data and determine the cellular localization of sirtuins in the retina, additional groups of human donor eyes with (n:34) or without glaucoma (n:20) were analyzed by triple immunofluorescence labeling of histological tissue sections with specific antibodies (including phospho-specific antibodies) to sirtuins (SIRT1, SIRT3, SIRT6, and SIRT7) and cell markers.
The high-throughput datasets obtained from quantitative LC-MS/MS analysis of the human retinal proteome included sirtuins (SIRT-2, 3, 4, 6, and 7), SIRT3 exhibiting over 2-fold increased expression (p<0.01) in glaucomatous samples. The Ingenuity Pathways Analysis defined the functional patterns and populated protein interaction networks. Parallel to the proteomics data, immunohistochemical analysis indicated sirtuin expression in retinal neurons and glia. Retinal immunolabeling for SIRT1, SIRT3, SIRT6, and SIRT7 exhibited the most prominent increase in the GFAP-positive astroglia in glaucomatous eyes relative to age-matched non-glaucomatous controls.
These findings reveal that sirtuins take part in cellular responses during glaucomatous neurodegeneration and motivate further research to determine the importance of sirtuins and the therapeutic potential of sirtuin modulators for neurodegenerative and neuroinflammatory outcomes in glaucoma.
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