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.

中文翻译：

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靶向mir128-3p可减轻心肌胰岛素抵抗并预防缺血性心力衰竭

心肌胰岛素抵抗响应病理应激而导致心力衰竭，因此，维持心脏胰岛素途径的治疗策略需要进一步研究。我们证明，在心肌梗死（MI）后衰竭的小鼠心脏和人心脏衰竭中，胰岛素受体底物1（IRS1）减少。MI后表现出严重心脏功能障碍的小鼠心肌中的mir128-3p升高。缺血上调的mir128-3p促进了Irs1降解。使用大鼠心肌细胞和人类诱导的多能干细胞衍生的心肌细胞，我们阐明了促分裂原激活的蛋白激酶7（MAPK7，也称为ERK5）介导的CCAAT /增强子结合蛋白β（CEBPβ）的转录抑制mir128-3p在缺氧条件下。治疗上，功能研究表明，基因治疗提供的心脏特异性MAPK7恢复或CEBPβ的过表达可抑制MI后心肌损伤，至少部分是由于mir128-3p的正常化所致。此外，对mir128-3p的抑制保留了Irs1，并改善了MI后的心脏功能障碍。总之，我们揭示了靶向mir128-3p可减轻心肌胰岛素抵抗，此后减缓缺血后心力衰竭的进展。