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C.E. Crosson, M.A. Haracznak, M.D. Covington, L. Xu, D.R. Menick; Histone Deacetylase Inhibitors Suppress Matrix Metalloproteinase Secretion from Human Optic Nerve Astrocytes . Invest. Ophthalmol. Vis. Sci. 2006;47(13):2618.
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Previous studies have provided evidence that the secretion and activation of matrix metalloproteinases (MMPs) from astocytes contributes to retinal damage induced by inflammation, and ischemic injury. The purpose of these studies was to investigate the impact of histone deacetylase (HDAC) inhibitors on matrix metalloproteinase expression induced by the inflammatory cytokine TNFα.
To stimulate MMP secretion from cultured primary human astrocytes cell were incubated with TNFα (10 ng/ml) for 24 hours. To investigate the role of HDACs cells were pretreated with the nonselective HDAC inhibitor trichostatin A (TSA; 10 –100 nM) for 1 hour prior to the addition of TNFα. The secretion of MMP–1 and –3 and histone–4 acetylation were determined by Western blot analysis. The expression of individual HDACs was determined by RT–PCR.
The addition of TNFα for 24 hours significantly increased the secretion of MMP–1 and MMP–3, over control levels, by 270% and 101%, respectively. Pretreatment with TSA (100 nM) blocked the TNFα–induced secretion MMP1 and MMP3. This inhibition by TSA was dose–related, with IC50s ranging from 10 to 22 nM. Treatment of astorcytes with TSA (100 nM) significantly increased histone–4 acetylation. RT–PCR analysis demonstrated that the principal HDACs expressed in human optic nerve astrocytes were HDAC2, 3, 6, and 8.
These studies demonstrate that the HDAC inhibitor TSA can block the induction and secretion of matrix metalloproteinases induced by the proinflammatory cytokine TNFα.. Hence, histone deacetylation may be an early required step in the expression and secretion of matrix metalloproteinase from optic nerve astrocytes. The use of HDAC inhibitors may provide a novel approach for the prevention and treatment of optic neuropathies.
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