Targeting <i>mir128-3p</i> alleviates myocardial insulin resistance and prevents ischemia-induced heart failure.

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 <i>mir128-3p</i> in the myocardium. Ischemia-upregulated <i>mir128-3p</i> promoted <i>Irs1</i> 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 <i>mir128-3p</i> 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 <i>mir128-3p</i>. Furthermore, inhibition of <i>mir128-3p</i> preserved <i>Irs1</i> and ameliorated cardiac dysfunction post-MI. In conclusion, we reveal that targeting <i>mir128-3p</i> mitigates myocardial insulin resistance, thereafter slowing down the progression of heart failure post-ischemia.