{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T01:44:14Z","timestamp":1760060654690,"version":"build-2065373602"},"reference-count":33,"publisher":"MDPI AG","issue":"17","license":[{"start":{"date-parts":[[2025,9,8]],"date-time":"2025-09-08T00:00:00Z","timestamp":1757289600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Swiss National Science Foundation","award":["310030_197557","320030-236150","739593","HA 7512\/2-4","HA 7512\/2-1"],"award-info":[{"award-number":["310030_197557","320030-236150","739593","HA 7512\/2-4","HA 7512\/2-1"]}]},{"name":"Swiss Heart Foundation","award":["310030_197557","320030-236150","739593","HA 7512\/2-4","HA 7512\/2-1"],"award-info":[{"award-number":["310030_197557","320030-236150","739593","HA 7512\/2-4","HA 7512\/2-1"]}]},{"name":"Novartis Foundation for Medical and Biological Research","award":["310030_197557","320030-236150","739593","HA 7512\/2-4","HA 7512\/2-1"],"award-info":[{"award-number":["310030_197557","320030-236150","739593","HA 7512\/2-4","HA 7512\/2-1"]}]},{"name":"Foundation for Scientific Research at the University of Zurich","award":["310030_197557","320030-236150","739593","HA 7512\/2-4","HA 7512\/2-1"],"award-info":[{"award-number":["310030_197557","320030-236150","739593","HA 7512\/2-4","HA 7512\/2-1"]}]},{"name":"Olga Mayenfisch Foundation","award":["310030_197557","320030-236150","739593","HA 7512\/2-4","HA 7512\/2-1"],"award-info":[{"award-number":["310030_197557","320030-236150","739593","HA 7512\/2-4","HA 7512\/2-1"]}]},{"name":"Swiss Life Foundation","award":["310030_197557","320030-236150","739593","HA 7512\/2-4","HA 7512\/2-1"],"award-info":[{"award-number":["310030_197557","320030-236150","739593","HA 7512\/2-4","HA 7512\/2-1"]}]},{"name":"Kurt und Senta-Hermann Stiftung","award":["310030_197557","320030-236150","739593","HA 7512\/2-4","HA 7512\/2-1"],"award-info":[{"award-number":["310030_197557","320030-236150","739593","HA 7512\/2-4","HA 7512\/2-1"]}]},{"name":"EMDO Stiftung and the Schweizerische Diabetes-Stiftung","award":["310030_197557","320030-236150","739593","HA 7512\/2-4","HA 7512\/2-1"],"award-info":[{"award-number":["310030_197557","320030-236150","739593","HA 7512\/2-4","HA 7512\/2-1"]}]},{"name":"Holcim Foundation","award":["310030_197557","320030-236150","739593","HA 7512\/2-4","HA 7512\/2-1"],"award-info":[{"award-number":["310030_197557","320030-236150","739593","HA 7512\/2-4","HA 7512\/2-1"]}]},{"name":"Gebauer Stiftung and the Swiss Heart Foundation","award":["310030_197557","320030-236150","739593","HA 7512\/2-4","HA 7512\/2-1"],"award-info":[{"award-number":["310030_197557","320030-236150","739593","HA 7512\/2-4","HA 7512\/2-1"]}]},{"name":"EU\u2019s Horizon 2020","award":["310030_197557","320030-236150","739593","HA 7512\/2-4","HA 7512\/2-1"],"award-info":[{"award-number":["310030_197557","320030-236150","739593","HA 7512\/2-4","HA 7512\/2-1"]}]},{"name":"DFG (Deutsche Forschungsgemeinschaft)","award":["310030_197557","320030-236150","739593","HA 7512\/2-4","HA 7512\/2-1"],"award-info":[{"award-number":["310030_197557","320030-236150","739593","HA 7512\/2-4","HA 7512\/2-1"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>MicroRNA 451 (miR-451) is emerging as a pivotal mediator of cardiac damage in experimental models of diabetic cardiomyopathy. Whether miR-451 plays a detrimental role in the human diabetic myocardium is unknown. The present study investigates miR-451\u2019s role in patients with type 2 diabetes (T2D). We show that miR-451 is upregulated in myocardial specimens from T2D patients compared to controls without diabetes and correlates with cardiometabolic parameters, the myocardial triglyceride content and cardiac expression of lipotoxic genes as well as echocardiographic indices of left ventricular dysfunction. Calcium-binding protein 39 (Cab39)\u2014a known target of miR-451 in mouse hearts\u2014was downregulated in T2D patients vs. controls, and its expression negatively correlated with that of miR-451. In cultured human cardiomyocytes (CMs), Ago2 immunoprecipitation confirmed Cab39 to be a direct target of miR-451. Treatment with a high amount of glucose (25mM) and palmitic acid (PA) mimicked miR-451 upregulation and Cab39 downregulation in human CMs. These changes were associated with increased TGs and markers of lipotoxic injury, such as elevated oxidative stress levels, mitochondrial dysfunction and apoptosis. Targeting miR-451 led to restoration of Cab39 levels while rescuing diabetes-induced lipotoxic injury and metabolic dysfunction. By contrast, miR-451 overexpression recapitulated features of lipotoxic damage. Our findings indicate miR-451 to be a potential target for the prevention of myocardial lipotoxic injury in diabetes.<\/jats:p>","DOI":"10.3390\/cells14171401","type":"journal-article","created":{"date-parts":[[2025,9,8]],"date-time":"2025-09-08T10:29:07Z","timestamp":1757327347000},"page":"1401","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["miR-451 Is a Driver of Lipotoxic Injury in Patients with Diabetic Cardiomyopathy"],"prefix":"10.3390","volume":"14","author":[{"given":"Sarah","family":"Costantino","sequence":"first","affiliation":[{"name":"Center for Translational and Experimental Cardiology (CTEC), Department of Cardiology, University Hospital Zurich and University of Z\u00fcrich, 8952 Schlieren, Switzerland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shafeeq A.","family":"Mohammed","sequence":"additional","affiliation":[{"name":"Center for Translational and Experimental Cardiology (CTEC), Department of Cardiology, University Hospital Zurich and University of Z\u00fcrich, 8952 Schlieren, Switzerland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Federico","family":"Ranocchi","sequence":"additional","affiliation":[{"name":"Department of Cardiac Surgery, Sant\u2019Andrea Hospital, \u201cSapienza\u201d University, Via di Grottarossa, 1035 Rome, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-0213-3651","authenticated-orcid":false,"given":"Francesco","family":"Zito","sequence":"additional","affiliation":[{"name":"Department of Cardiac Surgery, Sant\u2019Andrea Hospital, \u201cSapienza\u201d University, Via di Grottarossa, 1035 Rome, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Valentina","family":"Delfine","sequence":"additional","affiliation":[{"name":"Center for Translational and Experimental Cardiology (CTEC), Department of Cardiology, University Hospital Zurich and University of Z\u00fcrich, 8952 Schlieren, Switzerland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nazha","family":"Hamdani","sequence":"additional","affiliation":[{"name":"Institute of Physiology, Ruhr University, 44801 Bochum, Germany"},{"name":"Department of Molecular and Experimental Cardiology, Ruhr University, 44789 Bochum, Germany"},{"name":"Department of Cardiology, St-Josef Hospital, Ruhr University, 44791 Bochum, Germany"},{"name":"HCEMM-SU Cardiovascular Comorbidities Research Group, Center for Pharmacology and Drug Research & Development, Department of Pharmacology and Pharmacotherapy, Int\u00e9zet c\u00edme Semmelweis University, 1089 Budapest, Hungary"},{"name":"Department of Physiology, University Maastricht, 6211 LK Maastricht, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6323-147X","authenticated-orcid":false,"given":"Maria Cristina","family":"Vinci","sequence":"additional","affiliation":[{"name":"Centro Cardiologico Monzino IRCCS, Via C. Parea 4, 20138 Milan, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Giovanni","family":"Melina","sequence":"additional","affiliation":[{"name":"Department of Cardiac Surgery, Sant\u2019Andrea Hospital, \u201cSapienza\u201d University, Via di Grottarossa, 1035 Rome, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Francesco","family":"Paneni","sequence":"additional","affiliation":[{"name":"Center for Translational and Experimental Cardiology (CTEC), Department of Cardiology, University Hospital Zurich and University of Z\u00fcrich, 8952 Schlieren, Switzerland"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,9,8]]},"reference":[{"key":"ref_1","unstructured":"Collaborators GBDD (2023). Global, regional, and national burden of diabetes from 1990 to 2021, with projections of prevalence to 2050: A systematic analysis for the Global Burden of Disease Study 2021. 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