{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,29]],"date-time":"2026-10-29T08:03:38Z","timestamp":1793261018395,"version":"4.5.0"},"reference-count":41,"publisher":"MDPI AG","issue":"20","license":[{"start":{"date-parts":[[2019,10,17]],"date-time":"2019-10-17T00:00:00Z","timestamp":1571270400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003725","name":"National Research Foundation of Korea","doi-asserted-by":"publisher","award":["NRF-2015R1D1A1A01059630"],"award-info":[{"award-number":["NRF-2015R1D1A1A01059630"]}],"id":[{"id":"10.13039\/501100003725","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003725","name":"National Research Foundation of Korea","doi-asserted-by":"publisher","award":["NRF-2017M3A9E8023019"],"award-info":[{"award-number":["NRF-2017M3A9E8023019"]}],"id":[{"id":"10.13039\/501100003725","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Chonnam National University Hospital Biomedical Research Institute","award":["BCRI18019"],"award-info":[{"award-number":["BCRI18019"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>The current study was undertaken to investigate whether histone deacetylases (HDACs) can modulate the viability of retinal ganglion cells (RGCs) and the activity of glial cells in a mouse model of retinal ischemia-reperfusion (IR) injury. C57BL\/6J mice were subjected to constant elevation of intraocular pressure for 60 min to induce retinal IR injury. Expression of macroglial and microglial cell markers (GFAP and Iba1), hypoxia inducing factor (HIF)-1\u03b1, and histone acetylation was analyzed after IR injury. To investigate the role of HDACs in the activation of glial cells, overexpression of HDAC1 and HDAC2 isoforms was performed. To determine the effect of HDAC inhibition on RGC survival, trichostatin-A (TSA, 2.5 mg\/kg) was injected intraperitoneally. After IR injury, retinal GFAP, Iba1, and HIF-1\u03b1 were upregulated. Conversely, retinal histone acetylation was downregulated. Notably, adenoviral-induced overexpression of HDAC2 enhanced glial activation following IR injury, whereas overexpression of HDAC1 did not significantly affect glial activation. TSA treatment significantly increased RGC survival after IR injury. Our results suggest that increased activity of HDAC2 is closely related to glial activation in a mouse model of retinal IR injury and inhibition of HDACs by TSA showed neuroprotective potential in retinas with IR injuries.<\/jats:p>","DOI":"10.3390\/ijms20205159","type":"journal-article","created":{"date-parts":[[2019,10,18]],"date-time":"2019-10-18T04:12:59Z","timestamp":1571371979000},"page":"5159","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":19,"title":["HDAC2 Regulates Glial Cell Activation in Ischemic Mouse Retina"],"prefix":"10.3390","volume":"20","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7512-7303","authenticated-orcid":false,"given":"Mi Sun","family":"Sung","sequence":"first","affiliation":[{"name":"Department of Ophthalmology, Chonnam National University Medical School and Hospital, Gwangju 61469, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2169-8770","authenticated-orcid":false,"given":"Hwan","family":"Heo","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, Chonnam National University Medical School and Hospital, Gwangju 61469, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gwang Hyeon","family":"Eom","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Chonnam National University Medical School, Hwasungun 58128, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"So Young","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, Chonnam National University Medical School and Hospital, Gwangju 61469, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Helong","family":"Piao","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, Chonnam National University Medical School and Hospital, Gwangju 61469, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7078-9663","authenticated-orcid":false,"given":"Yue","family":"Guo","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, Chonnam National University Medical School and Hospital, Gwangju 61469, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sang Woo","family":"Park","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, Chonnam National University Medical School and Hospital, Gwangju 61469, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2019,10,17]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"16659","DOI":"10.1073\/pnas.0407643101","article-title":"Histone deacetylase inhibition-mediated neuronal differentiation of multipotent adult neural progenitor cells","volume":"101","author":"Hsieh","year":"2004","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"615","DOI":"10.1002\/(SICI)1521-1878(199808)20:8<615::AID-BIES4>3.0.CO;2-H","article-title":"Roles of histone acetyltransferases and deacetylases in gene regulation","volume":"20","author":"Kuo","year":"1998","journal-title":"Bioessays"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"539","DOI":"10.1038\/sj.cdd.4401769","article-title":"HATs and HDACs in neurodegeneration: A tale of disconcerted acetylation homeostasis","volume":"13","author":"Saha","year":"2006","journal-title":"Cell Death Differ."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"6537","DOI":"10.1093\/emboj\/cdg615","article-title":"Critical loss of CBP\/p300 histone acetylase activity by caspase-6 during neurodegeneration","volume":"22","author":"Rouaux","year":"2003","journal-title":"EMBO J."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"282","DOI":"10.1016\/j.neuroscience.2012.07.056","article-title":"Valproate promotes survival of retinal ganglion cells in a rat model of optic nerve crush","volume":"224","author":"Zhang","year":"2012","journal-title":"Neuroscience"},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Pelzel, H.R., Schlamp, C.L., and Nickells, R.W. (2010). Histone H4 deacetylation plays a critical role in early gene silencing during neuronal apoptosis. BMC Neurosci., 11.","DOI":"10.1186\/1471-2202-11-62"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"124","DOI":"10.1016\/j.exer.2014.07.012","article-title":"Acetylation: A lysine modification with neuroprotective effects in ischemic retinal degeneration","volume":"127","author":"Alsarraf","year":"2014","journal-title":"Exp. Eye Res."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"7486","DOI":"10.1167\/iovs.14-14792","article-title":"Acetylation preserves retinal ganglion cell structure and function in a chronic model of ocular hypertension","volume":"55","author":"Alsarraf","year":"2014","journal-title":"Invest. Ophthalmol. Vis. Sci."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"573","DOI":"10.1016\/0014-4835(91)90215-Z","article-title":"Quantitation of ischemic damage in the rat retina","volume":"53","author":"Hughes","year":"1991","journal-title":"Exp. Eye Res."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"2760","DOI":"10.1167\/iovs.03-1392","article-title":"Expression of apoptosis markers in the retinas of human subjects with diabetes","volume":"45","author":"Dralands","year":"2004","journal-title":"Invest. Ophthalmol. Vis. Sci."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1711","DOI":"10.1016\/S0140-6736(04)16257-0","article-title":"Primary open-angle glaucoma","volume":"363","author":"Weinreb","year":"2004","journal-title":"Lancet"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"102","DOI":"10.1016\/S0039-6257(99)00044-2","article-title":"Neuroprotection in relation to retinal ischemia and relevance to glaucoma","volume":"43","author":"Osborne","year":"1999","journal-title":"Surv. Ophthalmol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1385\/MN:26:1:045","article-title":"Neurobiology of glaucomatous optic neuropathy: Diverse cellular events in neurodegeneration and neuroprotection","volume":"26","author":"Wax","year":"2002","journal-title":"Mol. Neurobiol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"521","DOI":"10.1006\/exer.2002.2042","article-title":"Loss of retinal ganglion cells following retinal ischemia: The role of inducible nitric oxide synthase","volume":"75","author":"Neufeld","year":"2002","journal-title":"Exp. Eye Res."},{"key":"ref_15","first-page":"2038","article-title":"The role of neuronal and endothelial nitric oxide synthase in retinal excitotoxicity","volume":"38","author":"Vorwerk","year":"1997","journal-title":"Invest. Ophthalmol. Vis. Sci."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"637","DOI":"10.1017\/S0952523800010427","article-title":"Reduction of ocular blood flow results in glial fibrillary acidic protein (GFAP) expression in rat retinal M\u00fcller cells","volume":"7","author":"Osborne","year":"1991","journal-title":"Vis. Neurosci."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"3025","DOI":"10.1167\/iovs.02-1136","article-title":"Immunohistochemical assessment of the glial mitogen-activated protein kinase activation in glaucoma","volume":"44","author":"Tezel","year":"2003","journal-title":"Invest. Ophthalmol. Vis. Sci."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"203","DOI":"10.1016\/j.neuroscience.2007.06.053","article-title":"Valproic acid and other histone deacetylase inhibitors induce microglial apoptosis and attenuate lipopolysaccharide-induced dopaminergic neurotoxicity","volume":"149","author":"Chen","year":"2007","journal-title":"Neuroscience"},{"key":"ref_19","first-page":"4368","article-title":"Histone acetylation in astrocytes suppresses GFAP and stimulates a reorganization of the intermediate filament network","volume":"127","author":"Kanski","year":"2014","journal-title":"J. Cell Sci."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"4072","DOI":"10.1167\/iovs.12-11529","article-title":"Inhibition of HDAC2 protects the retina from ischemic injury","volume":"54","author":"Fan","year":"2013","journal-title":"Invest. Ophthalmol. Vis. Sci."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1019","DOI":"10.1016\/j.cell.2009.06.049","article-title":"Genome-wide mapping of HATs and HDACs reveals distinct functions in active and inactive genes","volume":"138","author":"Wang","year":"2009","journal-title":"Cell"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"767","DOI":"10.1016\/j.exer.2005.09.019","article-title":"Complex neurodegeneration in retina following moderate ischemia induced by bilateral common carotid artery occlusion in Wistar rats","volume":"82","author":"Yamamoto","year":"2006","journal-title":"Exp. Eye Res."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"63","DOI":"10.1016\/0014-4835(79)90106-4","article-title":"The radial glia of M\u00fcller in the rat retina and their response to injury. An immunofluorescence study with antibodies to the glial fibrillary acidic (GFA) protein","volume":"28","author":"Bignami","year":"1979","journal-title":"Exp. Eye Res."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"8693","DOI":"10.1523\/JNEUROSCI.20-23-08693.2000","article-title":"Increased production of tumor necrosis factor-alpha by glial cells exposed to simulated ischemia or elevated hydrostatic pressure induces apoptosis in cocultured retinal ganglion cells","volume":"20","author":"Tezel","year":"2000","journal-title":"J. Neurosci."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"168","DOI":"10.1016\/j.pharmthera.2014.02.012","article-title":"Posttranslational modifications of histone deacetylases: Implications for cardiovascular diseases","volume":"143","author":"Eom","year":"2014","journal-title":"Pharmacol. Ther."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"3115","DOI":"10.1167\/iovs.18-23826","article-title":"Trichostatin A ameliorates conjunctival fibrosis in a rat trabeculectomy model","volume":"59","author":"Sung","year":"2018","journal-title":"Invest. Ophthalmol. Vis. Sci."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"3639","DOI":"10.1167\/iovs.09-4538","article-title":"Inhibition of histone deacetylase protects the retina from ischemic injury","volume":"51","author":"Crosson","year":"2010","journal-title":"Invest. Ophthalmol. Vis. Sci."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1016\/j.neulet.2015.12.012","article-title":"Role of HDACs in optic nerve damage-induced nuclear atrophy of retinal ganglion cells","volume":"625","author":"Schmitt","year":"2016","journal-title":"Neurosci. Lett."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"269","DOI":"10.1016\/j.exer.2016.03.026","article-title":"Ischemic preconditioning, retinal neuroprotection and histone deacetylase activities","volume":"146","author":"Fan","year":"2016","journal-title":"Exp. Eye Res."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1038\/nature07925","article-title":"HDAC2 negatively regulates memory formation and synaptic plasticity","volume":"459","author":"Guan","year":"2009","journal-title":"Nature"},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Fritzsche, F.R., Weichert, W., R\u00f6ske, A., Gekeler, V., Beckers, T., Stephan, C., Jung, K., Scholman, K., Denkert, C., and Dietel, M. (2008). Class I histone deacetylases 1, 2 and 3 are highly expressed in renal cell cancer. BMC. Cancer., 8.","DOI":"10.1186\/1471-2407-8-381"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"566","DOI":"10.1038\/ng1773","article-title":"A truncating mutation of HDAC2 in human cancers confers resistance to histone deacetylase inhibition","volume":"38","author":"Ropero","year":"2006","journal-title":"Nat. Genet."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"604","DOI":"10.1038\/sj.bjc.6604199","article-title":"Histone deacetylases 1, 2 and 3 are highly expressed in prostate cancer and HDAC2 expression is associated with shorter PSA relapse time after radical prostatectomy","volume":"98","author":"Weichert","year":"2008","journal-title":"Br. J. Cancer"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"521","DOI":"10.1007\/s11481-010-9192-0","article-title":"Histone deacetylase inhibitors suppress the expression of inflammatory and innate immune response genes in human microglia and astrocytes","volume":"5","author":"Suh","year":"2010","journal-title":"J. Neuroimmune. Pharmacol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1133","DOI":"10.1002\/jnr.23221","article-title":"Histone deacetylase inhibitors suppress immune activation in primary mouse microglia","volume":"91","author":"Kannan","year":"2013","journal-title":"J. Neurosci. Res."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"2734","DOI":"10.1016\/j.fct.2011.08.012","article-title":"Anti-inflammatory effects of [6]-shogaol: Potential roles of HDAC inhibition and HSP70 induction","volume":"49","author":"Shim","year":"2011","journal-title":"Food Chem. Toxicol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"269","DOI":"10.1016\/j.nbd.2009.07.019","article-title":"Histone deacetylase (HDAC) inhibitors reduce the glial inflammatory response in vitro and in vivo","volume":"36","author":"Faraco","year":"2009","journal-title":"Neurobiol. Dis."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"214","DOI":"10.1111\/jnc.14144","article-title":"Inhibition of histone deacetylase 1 or 2 reduces induced cytokine expression in microglia through a protein synthesis independent mechanism","volume":"143","author":"Durham","year":"2017","journal-title":"J. Neurochem."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"737","DOI":"10.1042\/bj20021321","article-title":"Histone deacetylases (HDACs): Characterization of the classical HDAC family","volume":"370","author":"Caron","year":"2003","journal-title":"Biochem. J."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1016\/j.jmb.2004.02.006","article-title":"Molecular evolution of the histone deacetylase family: Functional implications of phylogenetic analysis","volume":"338","author":"Gregoretti","year":"2004","journal-title":"J. Mol. Biol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1186\/1750-1326-8-21","article-title":"Progressive morphological changes and impaired retinal function associated with temporal regulation of gene expression after retinal ischemia\/reperfusion injury in mice","volume":"8","author":"Kim","year":"2013","journal-title":"Mol. Neurodegener."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/20\/20\/5159\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T13:27:24Z","timestamp":1760189244000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/20\/20\/5159"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,10,17]]},"references-count":41,"journal-issue":{"issue":"20","published-online":{"date-parts":[[2019,10]]}},"alternative-id":["ijms20205159"],"URL":"https:\/\/doi.org\/10.3390\/ijms20205159","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,10,17]]}}}