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C. E. Crosson, M. Haracznak, D. R. Menick; Histone Deacetylase Inhibitor, TSA, Suppresses MMP-3 Secretion From Human Optic Nerve Astrocytes. Invest. Ophthalmol. Vis. Sci. 2007;48(13):3263.
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Previous studies have provided evidence that the secretion and activation of matrix metalloproteinases (MMPs) from astrocytes contribute to retinal damage induced by inflammation, ischemic injury, and glaucoma. The purpose of these studies was to investigate the role of acetylation - deacetylation on matrix metalloproteinase expression and secretion in primary cultures of human optic nerve astrocytes.
Primary human astrocyte cell cultures were established from optic nerve head explants. The expression patterns of histone deacetylases (HDACs) were determined by Western blot and PCR analysis. The effects of Class I and II HDAC inhibitor, TSA, on MMP-3 secretion and PI3-kinase/AKT pathway activation induced by, TNFα (10 ng/ml) were assessed by Western blot analysis.
Incubation of astrocytes with TNFα induced significant activation of the PI3-kinase/AKT pathway within 10 minutes, followed by a significant increase in MMP-3 secretion at 24 hours. Pretreatment with the PI3 kinase/AKT pathway inhibitor LY-294002 blocked the secretion of MMP-3. Western blot and PCR analysis identified HDAC1, 2, 3, 6, 9 and 11 as the principle histone deacetylates expressed in these cells. The nonselective HDAC inhibitor, TSA (100 nmol/L), blocked the expression and secretion of MMP-3 induced by TNFα. This inhibitory response was dose-related with IC50 of 21 nM. Pretreatment TSA (100 nmol/L) also blocked the activation of the PI3-kinase/Akt signaling pathway.
Protein acetylation - deacetylation appears to play a central role in the regulation of MMP-3 expression and secretion in optic nerve head astrocytes. These data provide evidence that this inhibitory response involves the suppression of normal PI3-kinase/Akt signaling. The use of HDAC inhibitors may provide a novel approach for the prevention and treatment of optic neuropathies.
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