Targeting mir128-3p alleviates myocardial insulin resistance and prevents ischemia-induced heart failure
- The University of Manchester, United Kingdom
- University of Kiel, Germany
- Technische Universität Dresden, Germany
- University of Edinburgh, United Kingdom
- Peking University, China
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.
Data availability
All data generated or analysed during this study are included in the manuscript and supporting files. Source data files have been provided for all figures.
Article and author information
Author details
Funding
British Heart Foundation (FS/15/16/31477)
- Wei Liu
British Heart Foundation (FS/18/73/33973)
- Wei Liu
British Heart Foundation (PG/12/76/29852)
- Xin Wang
British Heart Foundation (PG/14/71/310)
- Xin Wang
British Heart Foundation (PG/14/70/3103)
- Xin Wang
German Centre for Cardiovascular Research (81Z0700201)
- Oliver J Müller
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Animal experimentation: All animal studies were performed in accordance with the United Kingdom Animals (Scientific Procedures) Act 1986 under the Home Office license P3A97F3D1, and were approved by the University of Manchester Ethics Committee.
Copyright
© 2020, Ruiz-Velasco et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Targeting mir128-3p alleviates myocardial insulin resistance and prevents ischemia-induced heart failure
eLife 9:e54298.
https://doi.org/10.7554/eLife.54298
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