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JunD (Jund proto-oncogene subunit), a member of the AP-1 (activator protein-1) family of transcription factors, is emerging as a major gatekeeper against oxidative stress. However, its contribution to redox state and inflammation in the diabetic heart remains to be elucidated.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Objective:<\/jats:title>\n                    <jats:p>The present study investigates the role of JunD in hyperglycemia-induced and reactive oxygen species\u2013driven myocardial dysfunction.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods and Results:<\/jats:title>\n                    <jats:p>\n                      JunD mRNA and protein expression were reduced in the myocardium of mice with streptozotocin-induced diabetes mellitus as compared to controls. JunD downregulation was associated with oxidative stress and left ventricular dysfunction assessed by electron spin resonance spectroscopy as well as conventional and 2-dimensional speckle-tracking echocardiography. Furthermore, myocardial expression of free radical scavenger superoxide dismutase 1 and aldehyde dehydrogenase 2 was reduced, whereas the NOX2 (NADPH [nicotinamide adenine dinucleotide phosphatase] oxidase subunit 2) and NOX4 (NADPH [nicotinamide adenine dinucleotide phosphatase] oxidase subunit 4) were upregulated. The redox changes were associated with increased NF-\u03baB (nuclear factor kappa B) binding activity and expression of inflammatory mediators. Interestingly, mice with cardiac-specific overexpression of JunD via the \u03b1 MHC (\u03b1- myosin heavy chain) promoter (\u03b1 MHC\n                      <jats:italic>JunD<\/jats:italic>\n                      <jats:sup>\n                        <jats:italic>tg<\/jats:italic>\n                      <\/jats:sup>\n                      ) were protected against hyperglycemia-induced cardiac dysfunction. We also showed that JunD was epigenetically regulated by promoter hypermethylation, post-translational modification of histone marks, and translational repression by miRNA (microRNA)-673\/menin. Reduced JunD mRNA and protein expression were confirmed in left ventricular specimens obtained from patients with type 2 diabetes mellitus as compared to nondiabetic subjects.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions:<\/jats:title>\n                    <jats:p>Here, we show that a complex epigenetic machinery involving DNA methylation, histone modifications, and microRNAs mediates hyperglycemia-induced JunD downregulation and myocardial dysfunction in experimental and human diabetes mellitus. Our results pave the way for tissue-specific therapeutic modulation of JunD to prevent diabetic cardiomyopathy.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1161\/circresaha.120.317132","type":"journal-article","created":{"date-parts":[[2020,8,20]],"date-time":"2020-08-20T10:56:00Z","timestamp":1597920960000},"page":"1261-1273","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":67,"title":["Hyperglycemia Induces Myocardial Dysfunction via Epigenetic Regulation of JunD"],"prefix":"10.1161","volume":"127","author":[{"given":"Shafaat","family":"Hussain","sequence":"first","affiliation":[{"name":"Cardiology Unit, Department of Medicine Solna, Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden (S.H., A.W.K., R.S., C.H., C.G., J.P., L.H.L., F.C.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Abdul Waheed","family":"Khan","sequence":"additional","affiliation":[{"name":"Cardiology Unit, Department of Medicine Solna, Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden (S.H., A.W.K., R.S., C.H., C.G., J.P., L.H.L., F.C.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexander","family":"Akhmedov","sequence":"additional","affiliation":[{"name":"Center for Molecular Cardiology, University of Zurich, Switzerland (A.A., S.C., F.P., S.A.M., T.F.L.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0193-3115","authenticated-orcid":true,"given":"Rosa","family":"Suades","sequence":"additional","affiliation":[{"name":"Cardiology Unit, Department of Medicine Solna, Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden (S.H., A.W.K., R.S., C.H., C.G., J.P., L.H.L., F.C.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarah","family":"Costantino","sequence":"additional","affiliation":[{"name":"Center for Molecular Cardiology, University of Zurich, Switzerland (A.A., S.C., F.P., S.A.M., T.F.L.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesco","family":"Paneni","sequence":"additional","affiliation":[{"name":"Center for Molecular Cardiology, University of Zurich, Switzerland (A.A., S.C., F.P., S.A.M., T.F.L.)."},{"name":"University Heart Center and Department of Research and Education, University Hospital Z\u00fcrich, Switzerland (F.P.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kenneth","family":"Caidahl","sequence":"additional","affiliation":[{"name":"Department of Molecular Medicine and Surgery (K.C.), Karolinska Institutet, Stockholm, Sweden."},{"name":"Department of Molecular and Clinical Medicine, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Sweden (K.C.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2365-5037","authenticated-orcid":true,"given":"Shafeeq A.","family":"Mohammed","sequence":"additional","affiliation":[{"name":"Center for Molecular Cardiology, University of Zurich, Switzerland (A.A., S.C., F.P., S.A.M., T.F.L.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Camilla","family":"Hage","sequence":"additional","affiliation":[{"name":"Cardiology Unit, Department of Medicine Solna, Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden (S.H., A.W.K., R.S., C.H., C.G., J.P., L.H.L., F.C.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christos","family":"Gkolfos","sequence":"additional","affiliation":[{"name":"Cardiology Unit, Department of Medicine Solna, Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden (S.H., A.W.K., R.S., C.H., C.G., J.P., L.H.L., F.C.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hanna","family":"Bj\u00f6rck","sequence":"additional","affiliation":[{"name":"Center for Molecular Medicine, Department of 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