title: Acetylation: a lysine modification with neuroprotective effects in ischemic retinal degeneration.
abstract: Neuroretinal ischemic injury contributes to several degenerative diseases in the eye and the resulting pathogenic processes involving a series of necrotic and apoptotic events. This study investigates the time and extent of changes in acetylation, and whether this influences function and survival of neuroretinal cells following injury. Studies evaluated the time course of changes in histone deacetylase (HDAC) activity, histone-H3 acetylation and caspase-3 activation levels as well as retinal morphology and function (electroretinography) following ischemia. In addition, the effect of two HDAC inhibitors, trichostatin-A and valproic acid were also investigated. In normal eyes, retinal ischemia produced a significant increase in HDAC activity within 2 h that was followed by a corresponding significant decrease in protein acetylation by 4 h. Activated caspase-3 levels were significantly elevated by 24 h. Treatment with HDAC inhibitors blocked the early decrease in protein acetylation and activation of caspase-3. Retinal immunohistochemistry demonstrated that systemic administration of trichostatin-A or valproic acid, resulted in hyperacetylation of all retinal layers after systemic treatment. In addition, HDAC inhibitors provided a significant functional and structural neuroprotection at seven days following injury relative to vehicle-treated eyes. These results provide evidence that increases in HDAC activity is an early event following retinal ischemia, and are accompanied by corresponding decreases in acetylation in advance of caspase-3 activation. In addition to preserving acetylation status, the administration of HDAC inhibitors suppressed caspase activation and provided structural and functional neuroprotection in model of ischemic retinal injury. Taken together these data provide evidence that decrease in retinal acetylation status is a central event in ischemic retinal injury, and the hyperacetylation induced by HDAC inhibition can provide acute neuroprotection.
authors: 167 Ashley Avenue, Storm Eye Institute, Department of Ophthalmology, Medical University of South Carolina, Charleston, SC 29425, USA.
authors: Oday
authors: O
authors: Alsarraf
authors: 167 Ashley Avenue, Storm Eye Institute, Department of Ophthalmology, Medical University of South Carolina, Charleston, SC 29425, USA. Electronic address: fan@musc.edu.
authors: Jie
authors: J
authors: Fan
authors: 167 Ashley Avenue, Storm Eye Institute, Department of Ophthalmology, Medical University of South Carolina, Charleston, SC 29425, USA.
authors: Mohammad
authors: M
authors: Dahrouj
authors: 167 Ashley Avenue, Storm Eye Institute, Department of Ophthalmology, Medical University of South Carolina, Charleston, SC 29425, USA.
authors: C James
authors: CJ
authors: Chou
authors: 167 Ashley Avenue, Storm Eye Institute, Department of Ophthalmology, Medical University of South Carolina, Charleston, SC 29425, USA.
authors: Donald R
authors: DR
authors: Menick
authors: 167 Ashley Avenue, Storm Eye Institute, Department of Ophthalmology, Medical University of South Carolina, Charleston, SC 29425, USA.
authors: Craig E
authors: CE
authors: Crosson
mesh_terms: D000107:Acetylation; D000818:Animals; D015153:Blotting, Western; D053148:Caspase 3 / Q000378:metabolism*; D002470:Cell Survival; D004596:Electroretinography; D005260:Female; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006655:Histone Deacetylases / Q000378:metabolism*; D006657:Histones / Q000378:metabolism*; D006877:Hydroxamic Acids / Q000494:pharmacology; D008239:Lysine / Q000378:metabolism*; D008297:Male; D018696:Neuroprotective Agents / Q000494:pharmacology; D011914:Rats, Inbred BN; D015427:Reperfusion Injury / Q000201:enzymology / Q000503:physiopathology / Q000517:prevention & control*; D012162:Retinal Degeneration / Q000201:enzymology / Q000503:physiopathology / Q000517:prevention & control*; D055351:Retinal Neurons / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D014635:Valproic Acid / Q000494:pharmacology
chemical_list: D056572:Histone Deacetylase Inhibitors; D006657:Histones; D006877:Hydroxamic Acids; D018696:Neuroprotective Agents; C012589:trichostatin A; D014635:Valproic Acid; D053148:Caspase 3; D006655:Histone Deacetylases; D008239:Lysine
keywords: HDAC; acetylation; ischemia; neuroprotection; retina