Abstract
Histone acetylation was significantly increased in retinas from diabetic rats, and this acetylation was inhibited in diabetics treated with minocycline, a drug known to inhibit early diabetic retinopathy in animals. Histone acetylation and expression of inflammatory proteins that have been implicated in the pathogenesis of diabetic retinopathy were increased likewise in cultured retinal Müller glia grown in a diabetes-like concentration of glucose. Both the acetylation and induction of the inflammatory proteins in elevated glucose levels were significantly inhibited by inhibitors of histone acetyltransferase (garcinol and antisense against the histone acetylase, p300) or activators of histone deacetylase (theophylline and resveratrol) and were increased by the histone deacetylase inhibitor, suberolylanilide hydroxamic acid. We conclude that hyperglycemia causes acetylation of retinal histones (and probably other proteins) and that the acetylation contributes to the hyperglycemia-induced up-regulation of proinflammatory proteins and thereby to the development of diabetic retinopathy.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, Non-P.H.S.
MeSH terms
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Acetylation / drug effects
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Amino Acid Sequence
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Animals
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Cell Line
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Diabetes Mellitus, Experimental / drug therapy
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Diabetes Mellitus, Experimental / enzymology
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Diabetes Mellitus, Experimental / metabolism
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Diabetic Retinopathy / drug therapy
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Diabetic Retinopathy / enzymology
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Diabetic Retinopathy / metabolism
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Histone Acetyltransferases / antagonists & inhibitors
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Histone Acetyltransferases / metabolism*
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Histone Deacetylase Inhibitors / pharmacology
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Histone Deacetylases / metabolism*
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Histones / chemistry
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Histones / metabolism*
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Inflammation Mediators / metabolism
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Intercellular Adhesion Molecule-1 / genetics
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Intercellular Adhesion Molecule-1 / metabolism
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Male
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Minocycline / pharmacology*
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Minocycline / therapeutic use
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Molecular Sequence Data
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Nitric Oxide Synthase Type II / genetics
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Nitric Oxide Synthase Type II / metabolism
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Peptide Fragments / chemistry
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Protein Processing, Post-Translational*
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Rats
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Rats, Inbred Lew
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Retina / drug effects
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Retina / enzymology
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Retina / metabolism
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Tandem Mass Spectrometry
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Terpenes / pharmacology
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Vascular Endothelial Growth Factor A / genetics
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Vascular Endothelial Growth Factor A / metabolism
Substances
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Histone Deacetylase Inhibitors
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Histones
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Inflammation Mediators
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Peptide Fragments
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Terpenes
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Vascular Endothelial Growth Factor A
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vascular endothelial growth factor A, rat
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Intercellular Adhesion Molecule-1
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Nitric Oxide Synthase Type II
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Nos2 protein, rat
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Histone Acetyltransferases
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Histone Deacetylases
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Minocycline
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garcinol