Targeting mir128-3p alleviates myocardial insulin resistance and prevents ischemia-induced heart failure

eLife

Oliver J Müller¹  Susanne S Hille¹  Norbert Frey¹  Fay Pu²  Pablo Binder³  Lucy Collins³  Wei Liu³  Juwei Jiang³  Elizabeth J Cartwright³  Min Zi³  Tayyiba Azam³  Xin Wang³  Namrita Kaur³  Andrea Ruiz-Velasco³  Binh Nguyen³  Karolina Sekeres⁴  Kaomei Guan⁴  Han Xiao⁵ 

[1] Department of Internal Medicine III, University of Kiel, Kiel, Germany;DZHK, German Centre for Cardiovascular Research, Partner Site Hamburg/Kiel/Lübeck, Kiel, Germany;Edinburgh University Medical School, Edinburgh, United Kingdom;Faculty of Biology, Medicine, and Health, the University of Manchester, Manchester, United Kingdom;Institute of Pharmacology and Toxicology, Faculty of Medicine Carl Gustav Carus, Technische Universitaet Dresden, Dresden, Germany;Institute of Vascular Medicine, Peking University, Beijing, China;

关键词: cardioprotection;    myocardial infarction;    cardiac insulin resistance;    IRS1;    miRNA;    Mouse;    Rat;   

DOI  :  10.7554/eLife.54298

来源: publisher

【 摘 要 】

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.

【 授权许可】

CC BY