{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,12]],"date-time":"2026-10-12T23:32:50Z","timestamp":1791847970869,"version":"4.3.4"},"reference-count":32,"publisher":"Wiley","issue":"6","license":[{"start":{"date-parts":[[2015,2,25]],"date-time":"2015-02-25T00:00:00Z","timestamp":1424822400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Journal Cellular Physiology"],"published-print":{"date-parts":[[2015,6]]},"abstract":"<jats:sec><jats:label\/><jats:p>Histone deacetylases (HDACs) play a crucial role in the regulation of gene expression through remodeling of chromatin structures. However, the molecular mechanisms involved in this event remain unknown. In this study, we sought to examine whether HDAC inhibition\u2010mediated protective effects involved HDAC4 sumoylation, degradation, and the proteasome pathway. Isolated neonatal mouse ventricular myocytes (NMVM) and H9c2 cardiomyoblasts were subjected to 48\u2009h of hypoxia (H) (1% O<jats:sub>2<\/jats:sub>) and 2\u2009h of reoxygenation (R). Treatment of cardiomyocytes with trichostatin A (TSA) attenuated H\/R\u2010elicited injury, as indicated by a reduction of lactate dehydrogenase (LDH) leakage, an increase in cell viability, and decrease in apoptotic positive cardiomyocytes. MG132, a potent proteasome pathway inhibitor, abrogated TSA\u2010induced protective effects, which was associated with the accumulation of ubiquitinated HDAC4. NMVM transduced with adenoviral HDAC4 led to an exaggeration of H\/R\u2010induced injury. TSA treatment resulted in a decrease in HDAC4 in cardiomyocytes infected with adenoviral HDAC4, and HDAC4\u2010induced injury was attenuated by TSA. HDAC inhibition resulted in a significant reduction in reactive oxygen species (ROS) in cardiomyoblasts exposed to H\/R, which was attenuated by blockade of the proteasome pathway. Cardiomyoblasts carrying wild type and sumoylation mutation (K559R) were established to examine effects of HDAC4 sumoylation and ubiquitination on H\/R injury. Disruption of HDAC4 sumoylation brought about HDAC4 accumulation and impairment of HDAC4 ubiquitination in association with enhanced susceptibility of cardiomyoblasts to H\/R. Taken together, these results demonstrated that HDAC inhibition stimulates proteasome dependent degradation of HDAC4, which is associated with HDAC4 sumoylation to induce these protective effects. J. Cell. Physiol. 230: 1321\u20131331, 2015. \u00a9 2014 Wiley Periodicals, Inc., A Wiley Company<\/jats:p><\/jats:sec>","DOI":"10.1002\/jcp.24871","type":"journal-article","created":{"date-parts":[[2014,12,9]],"date-time":"2014-12-09T01:30:12Z","timestamp":1418088612000},"page":"1321-1331","source":"Crossref","is-referenced-by-count":48,"title":["HDAC4 Degradation Mediates HDAC Inhibition\u2010Induced Protective Effects Against Hypoxia\/Reoxygenation Injury"],"prefix":"10.1002","volume":"230","author":[{"given":"Jianfeng","family":"Du","sequence":"first","affiliation":[{"name":"Department of Surgery Boston University Medical School Boston University Roger Williams Medical Center Providence Rhode Island"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ling","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Emergency Medicine Rhode Island Hospital Brown Medical School Brown University Providence Rhode 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