Faculty of Biology, Medicine, and Health, the University of Manchester, Manchester, United Kingdom.
Department of Internal Medicine III, University of Kiel, Kiel, Germany.
Elife. 2020 Mar 30;9:e54298. doi: 10.7554/eLife.54298.
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 in the myocardium. Ischemia-upregulated promoted 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 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 . Furthermore, inhibition of preserved and ameliorated cardiac dysfunction post-MI. In conclusion, we reveal that targeting mitigates myocardial insulin resistance, thereafter slowing down the progression of heart failure post-ischemia.
心肌胰岛素抵抗导致心力衰竭对病理压力的反应，因此，需要进一步研究维持心脏胰岛素途径的治疗策略。我们证明，胰岛素受体底物 1 (IRS1) 在心肌梗死后的衰竭小鼠心脏和衰竭的人类心脏中减少。在心肌梗死后表现出严重心脏功能障碍的小鼠，心肌中的 升高。缺血上调的 促进了 降解。使用大鼠心肌细胞和人诱导多能干细胞衍生的心肌细胞，我们阐明了丝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）在缺氧下转录抑制 。在治疗上，功能研究表明，心脏特异性 MAPK7 恢复的基因治疗或 CEBPβ 的过表达阻止了 MI 后的心脏损伤，至少部分原因是 的正常化。此外， 抑制可保留 和改善 MI 后的心脏功能障碍。总之，我们揭示了靶向 的作用可以减轻心肌胰岛素抵抗，从而减缓缺血后心力衰竭的进展。
