Targeting mir128-3p alleviates myocardial insulin resistance and prevents ischemia-induced heart failure: javascript:void(0);

Andrea Ruiz-velasco, Min Zi, Susanne S Hille, Tayyiba Azam, Namrita Kaur, Juwei Jiang, Binh Nguyen, Karolina Sekeres, Pablo Binder, Lucy Collins, Fay Pu, Han Xiao, Kaomei Guan, Norbert Frey, Elizabeth J Cartwright, Oliver J Müller, Xin Wang, Wei Liu

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish
JournaleLife
Volume9
Early online date30 Mar 2020
DOIs
Publication statusE-pub ahead of print - 30 Mar 2020

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