eLife (Mar 2020)

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

  • 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

DOI
https://doi.org/10.7554/eLife.54298
Journal volume & issue
Vol. 9

Abstract

Read online

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.

Keywords