{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T23:55:14Z","timestamp":1790207714874,"version":"4.1.0"},"reference-count":49,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"7","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circulation"],"published-print":{"date-parts":[[2019,8,13]]},"abstract":"<jats:sec>\n            <jats:title>Background:<\/jats:title>\n            <jats:p>Worldwide, diabetes mellitus and heart failure represent frequent comorbidities with high socioeconomic impact and steadily growing incidence, calling for a better understanding of how diabetic metabolism promotes cardiac dysfunction. Paradoxically, some glucose-lowering drugs have been shown to worsen heart failure, raising the question of how glucose mediates protective versus detrimental cardiac signaling. Here, we identified a histone deacetylase 4 (HDAC4) subdomain as a molecular checkpoint of adaptive and maladaptive signaling in the diabetic heart.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Methods:<\/jats:title>\n            <jats:p>\n              A conditional HDAC4 allele was used to delete HDAC4 specifically in cardiomyocytes (HDAC4-knockout). Mice were subjected to diabetes mellitus either by streptozotocin injections (type 1 diabetes mellitus model) or by crossing into mice carrying a leptin receptor mutation (db\/db; type 2 diabetes mellitus model) and monitored for remodeling and cardiac function. Effects of glucose and the posttranslational modification by \u03b2-linked\n              <jats:italic>N<\/jats:italic>\n              -acetylglucosamine (O-GlcNAc) on HDAC4 were investigated in vivo and in vitro by biochemical and cellular assays.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Results:<\/jats:title>\n            <jats:p>\n              We show that the cardio-protective N-terminal proteolytic fragment of HDAC4 is enhanced in vivo in patients with diabetes mellitus and mouse models, as well as in vitro under high-glucose and high\u2013O-GlcNAc conditions. HDAC4-knockout mice develop heart failure in models of type 1 and type 2 diabetes mellitus, whereas wild-type mice do not develop clear signs of heart failure, indicating that HDAC4 protects the diabetic heart. Reexpression of the N-terminal fragment of HDAC4 prevents HDAC4-dependent diabetic cardiomyopathy. Mechanistically, the posttranslational modification of HDAC4 at serine (Ser)-642 by O-GlcNAcylation is an essential step for production of the N-terminal fragment of HDAC4, which was attenuated by Ca\n              <jats:sup>2+<\/jats:sup>\n              \/calmodulin\u2013dependent protein kinase II\u2013mediated phosphorylation at Ser-632. Preventing O-GlcNAcylation at Ser-642 not only entirely precluded production of the N-terminal fragment of HDAC4 but also promoted Ca\n              <jats:sup>2+<\/jats:sup>\n              \/calmodulin\u2013dependent protein kinase II\u2013mediated phosphorylation at Ser-632, pointing to a mutual posttranslational modification cross talk of (cardio-detrimental) phosphorylation at Ser-632 and (cardio-protective) O-GlcNAcylation at Ser-642.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusions:<\/jats:title>\n            <jats:p>\n              In this study, we found that O-GlcNAcylation of HDAC4 at Ser-642 is cardio-protective in diabetes mellitus and counteracts pathological Ca\n              <jats:sup>2+<\/jats:sup>\n              \/calmodulin\u2013dependent protein kinase II signaling. We introduce a molecular model explaining how diabetic metabolism possesses important cardio-protective features besides its known detrimental effects. A deeper understanding of the here-described posttranslational modification cross talk may lay the groundwork for the development of specific therapeutic concepts to treat heart failure in the context of diabetes mellitus.\n            <\/jats:p>\n          <\/jats:sec>","DOI":"10.1161\/circulationaha.117.031942","type":"journal-article","created":{"date-parts":[[2019,6,14]],"date-time":"2019-06-14T09:00:20Z","timestamp":1560502820000},"page":"580-594","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":122,"title":["O-GlcNAcylation of Histone Deacetylase 4 Protects the Diabetic Heart From Failure"],"prefix":"10.1161","volume":"140","author":[{"given":"Mariya","family":"Kronlage","sequence":"first","affiliation":[{"name":"Institute of Experimental Cardiology (M.K., M.D., J.G., U.O., L.H.L., J.B.), Heidelberg University, Germany."},{"name":"Department of Cardiology (M.K., L.H.L., O.J.M., H.A.K.), Heidelberg University, Germany."},{"name":"German Centre for Cardiovascular Research (DZHK), partner site Heidelberg\/Mannheim (M.K., M.D., J.G., U.O., L.H.L., J.B., L.H.L., O.J.M., H.A.K.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthias","family":"Dewenter","sequence":"additional","affiliation":[{"name":"Institute of Experimental Cardiology (M.K., M.D., J.G., U.O., L.H.L., J.B.), Heidelberg University, Germany."},{"name":"German Centre for Cardiovascular Research (DZHK), partner site Heidelberg\/Mannheim (M.K., M.D., J.G., U.O., L.H.L., J.B., L.H.L., O.J.M., H.A.K.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Johannes","family":"Grosso","sequence":"additional","affiliation":[{"name":"Institute of Experimental Cardiology (M.K., M.D., J.G., U.O., L.H.L., J.B.), Heidelberg University, Germany."},{"name":"German Centre for Cardiovascular Research (DZHK), partner site Heidelberg\/Mannheim (M.K., M.D., J.G., U.O., L.H.L., J.B., L.H.L., O.J.M., H.A.K.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas","family":"Fleming","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine I (T.F.), Heidelberg University, Germany."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ulrike","family":"Oehl","sequence":"additional","affiliation":[{"name":"Institute of Experimental Cardiology (M.K., M.D., J.G., U.O., L.H.L., J.B.), Heidelberg University, Germany."},{"name":"German Centre for Cardiovascular Research (DZHK), partner site Heidelberg\/Mannheim (M.K., M.D., J.G., U.O., L.H.L., J.B., L.H.L., O.J.M., H.A.K.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lorenz H.","family":"Lehmann","sequence":"additional","affiliation":[{"name":"Institute of Experimental Cardiology (M.K., M.D., J.G., U.O., L.H.L., J.B.), Heidelberg University, Germany."},{"name":"Department of Cardiology (M.K., L.H.L., O.J.M., H.A.K.), Heidelberg University, Germany."},{"name":"German Centre for Cardiovascular Research (DZHK), partner site Heidelberg\/Mannheim (M.K., M.D., J.G., U.O., L.H.L., J.B., L.H.L., O.J.M., H.A.K.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"In\u00eas","family":"Falc\u00e3o-Pires","sequence":"additional","affiliation":[{"name":"Unidade de Investiga\u00e7\u00e3o Cardiovascular, Departamento de Cirurgia e Fisiologia, Faculdade de Medicina, Universidade do Porto, Portugal (I.F.-P., A.F.L.-M.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adelino F.","family":"Leite-Moreira","sequence":"additional","affiliation":[{"name":"Unidade de Investiga\u00e7\u00e3o Cardiovascular, Departamento de Cirurgia e Fisiologia, Faculdade de Medicina, Universidade do Porto, Portugal (I.F.-P., A.F.L.-M.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nadine","family":"Volk","sequence":"additional","affiliation":[{"name":"Tissue Bank of the National Center for Tumor Diseases, Heidelberg, Germany (N.V.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hermann-Josef","family":"Gr\u00f6ne","sequence":"additional","affiliation":[{"name":"Department of Cellular and Molecular Pathology, German Cancer Research Center, Heidelberg (H.-J.G.)."},{"name":"Institute of Pathology, University of Marburg, Germany (H.-J.G.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Oliver J.","family":"M\u00fcller","sequence":"additional","affiliation":[{"name":"Department of Cardiology (M.K., L.H.L., O.J.M., H.A.K.), Heidelberg University, Germany."},{"name":"German Centre for Cardiovascular Research (DZHK), partner site Heidelberg\/Mannheim (M.K., M.D., J.G., U.O., L.H.L., J.B., L.H.L., O.J.M., H.A.K.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Albert","family":"Sickmann","sequence":"additional","affiliation":[{"name":"Leibniz Institute for Analysical Sciences (ISAS), Dortmund, Germany (A.S.)."},{"name":"Medical Faculty, Medical Proteomics Center, Ruhr-University Bochum, Germany (A.S.)."},{"name":"Department of Chemistry, College of Physical Sciences, University of Aberdeen, United Kingdom (A.S.). Dr M\u00fcller is currently at the Department of Internal Medicine III, University of Kiel, Germany."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hugo A.","family":"Katus","sequence":"additional","affiliation":[{"name":"Department of Cardiology (M.K., L.H.L., O.J.M., H.A.K.), Heidelberg University, Germany."},{"name":"German Centre for Cardiovascular Research (DZHK), partner site Heidelberg\/Mannheim (M.K., M.D., J.G., U.O., L.H.L., J.B., L.H.L., O.J.M., H.A.K.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Johannes","family":"Backs","sequence":"additional","affiliation":[{"name":"Institute of Experimental Cardiology (M.K., M.D., J.G., U.O., L.H.L., J.B.), Heidelberg University, Germany."},{"name":"German Centre for Cardiovascular Research (DZHK), partner site Heidelberg\/Mannheim (M.K., M.D., J.G., U.O., L.H.L., J.B., L.H.L., O.J.M., 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