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Fiona McDonnell, Abbot F Clark, Colm J O'Brien, Deborah M Wallace; The Role of Hypoxia in Inducing Aberrant Epigenetic and Fibrotic States in Glaucoma. Invest. Ophthalmol. Vis. Sci. 2014;55(13):5716.
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Current treatment for glaucoma focuses on lowering intraocular pressure (IOP), but despite well-controlled IOP some patients continue to suffer progressive damage. Other possible methods of treatment may include targeting underlying factors, such as fibrosis. One of the areas affected by fibrosis in glaucoma is the lamina cribrosa (LC) which shows increased expression of pro-fibrotic genes such as transforming growth factor β (TGFβ), collagen 1a1 (COL1a1) and α-smooth muscle actin (αSMA). This area is also subjected to a hypoxic environment in glaucoma. Hypoxia has been shown to induce epigenetic changes in other fibrotic diseases and may have a similar effect in glaucoma. The aim of this study was to subject LC cells to hypoxia to determine if the epigenetic profile was altered and if there was a subsequent change in the expression of fibrotic genes.
Primary human LC cells from normal donors were subjected to hypoxia (1%O2) for 6 and 24 hours to examine if global DNA methylation and expression of DNA methyltransferases (DNMTs) and methyl CpG binding protein 2 (MeCP2) were altered when compared to normoxic cells (21%O2). We also wanted to determine if fibrotic genes were altered by hypoxia, to do this we examined the gene expression of the anti-fibrotic Ras protein activator like-1 (RASAL1), and the profibrotic genes αSMA and TGFβ1.
At 6 hours hypoxia significantly increased the level of global DNA methylation in LC cells (HLC) compared to normoxic LC cells (NLC) (P<0.05) and qPCR analysis showed that hypoxia increased DNMT1 (P<0.05), DNMT3A, MeCP2 (P<0.05), TGFβ1 (P=0.01), αSMA (P<0.01) and RASAL1 (P<0.05). Global DNA methylation was also increased at 24 hours in HLC cells (P<0.01). After 24 hours of hypoxia, DNMT1 (P<0.01), MeCP2 (P<0.05) and RASAL1 (P<0.01) were decreased, whereas DNMT3A and αSMA were increased and TGFβ1 expression returned to baseline.
We have shown that the hypoxic environment in glaucoma may affect epigenetic mechanisms, and furthermore, that genes related to fibrosis are also affected by hypoxia in these cells. This may give a new avenue for treatment using available epigenetic modulators to alter the fibrotic phenotype seen in glaucoma.
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