| Zdroj: |
Ruiz-velasco, A, Zi, M, Hille, S S, Azam, T, Kaur, N, Jiang, J, Nguyen, B, Sekeres, K, Binder, P, Collins, L, Pu, F, Xiao, H, Guan, K, Frey, N, Cartwright, E J, Müller, O J, Wang, X & Liu, W 2020, ' Targeting mir128-3p alleviates myocardial insulin resistance and prevents ischemia-induced heart failure : javascript:void(0); ', eLife, vol. 9 . https://doi.org/10.7554/eLife.54298, https://doi.org/10.7554/eLife.54298 |
| Popis: |
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. |
