Faculty of Biology, Medicine, and Health, the University of Manchester, Manchester, United Kingdom
Min Zi
Faculty of Biology, Medicine, and Health, the University of Manchester, Manchester, United Kingdom
Susanne S Hille
Department of Internal Medicine III, University of Kiel, Kiel, Germany; DZHK, German Centre for Cardiovascular Research, Partner Site Hamburg/Kiel/Lübeck, Kiel, Germany
Tayyiba Azam
Faculty of Biology, Medicine, and Health, the University of Manchester, Manchester, United Kingdom
Namrita Kaur
Faculty of Biology, Medicine, and Health, the University of Manchester, Manchester, United Kingdom
Juwei Jiang
Faculty of Biology, Medicine, and Health, the University of Manchester, Manchester, United Kingdom
Binh Nguyen
Faculty of Biology, Medicine, and Health, the University of Manchester, Manchester, United Kingdom
Karolina Sekeres
Institute of Pharmacology and Toxicology, Faculty of Medicine Carl Gustav Carus, Technische Universitaet Dresden, Dresden, Germany
Pablo Binder
Faculty of Biology, Medicine, and Health, the University of Manchester, Manchester, United Kingdom
Lucy Collins
Faculty of Biology, Medicine, and Health, the University of Manchester, Manchester, United Kingdom
Fay Pu
Edinburgh University Medical School, Edinburgh, United Kingdom
Han Xiao
Institute of Vascular Medicine, Peking University, Beijing, China
Kaomei Guan
Institute of Pharmacology and Toxicology, Faculty of Medicine Carl Gustav Carus, Technische Universitaet Dresden, Dresden, Germany
Norbert Frey
Department of Internal Medicine III, University of Kiel, Kiel, Germany; DZHK, German Centre for Cardiovascular Research, Partner Site Hamburg/Kiel/Lübeck, Kiel, Germany
Elizabeth J Cartwright
Faculty of Biology, Medicine, and Health, the University of Manchester, Manchester, United Kingdom
Oliver J Müller
Department of Internal Medicine III, University of Kiel, Kiel, Germany; DZHK, German Centre for Cardiovascular Research, Partner Site Hamburg/Kiel/Lübeck, Kiel, Germany
Xin Wang
Faculty of Biology, Medicine, and Health, the University of Manchester, Manchester, United Kingdom
Myocardial insulin resistance contributes to heart failure in response to pathological stresses, therefore, a therapeutic strategy to maintain cardiac insulin pathways requires further investigation. We demonstrated that insulin receptor substrate 1 (IRS1) was reduced in failing mouse hearts post-myocardial infarction (MI) and failing human hearts. The mice manifesting severe cardiac dysfunction post-MI displayed elevated mir128-3p in the myocardium. Ischemia-upregulated mir128-3p promoted Irs1 degradation. Using rat cardiomyocytes and human-induced pluripotent stem cell-derived cardiomyocytes, we elucidated that mitogen-activated protein kinase 7 (MAPK7, also known as ERK5)-mediated CCAAT/enhancer-binding protein beta (CEBPβ) transcriptionally represses mir128-3p under hypoxia. Therapeutically, functional studies demonstrated gene therapy-delivered cardiac-specific MAPK7 restoration or overexpression of CEBPβ impeded cardiac injury after MI, at least partly due to normalization of mir128-3p. Furthermore, inhibition of mir128-3p preserved Irs1 and ameliorated cardiac dysfunction post-MI. In conclusion, we reveal that targeting mir128-3p mitigates myocardial insulin resistance, thereafter slowing down the progression of heart failure post-ischemia.