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 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.
Highlights
Ischemic heart disease is a leading cause of mortality worldwide (Benjamin et al, 2019)
We focused on analyzing the key genes involved in cardiac glucose metabolism, revealing that a significant number of genes responsible for glucose uptake and glycolysis were differentially expressed in the failing hearts post-myocardial infarction (MI) (Figure 1E)
insulin receptor substrate 1 (IRS1) was prominently decreased, which was validated by quantitative PCR and immunoblots (Figure 1F and G); the levels of other factors involved in glucose uptake (Insr, Slc2a4, and Slc2a1) were not significantly changed (Figure 1F and G)
Summary
Ischemic heart disease is a leading cause of mortality worldwide (Benjamin et al, 2019). Significant advances in treatment have improved early survival after myocardial infarction (MI), such as bypass surgery, percutaneous coronary intervention, and thrombolytic therapy, the high prevalence of post-MI-associated heart failure (HF) remains (Sanchis-Gomar et al, 2016). Clinical studies suggest that promoting reliance on glucose under ischemic condition represents an indispensable adaption, which may have beneficial effects on survival in patients suffering from ischemic heart disease (Montessuit and Lerch, 2013; Ritterhoff and Tian, 2017). At an early stage post-ischemia, enhanced insulin-dependent glucose utilization in cardiomyocytes protects the heart against injury exacerbation (Nagoshi et al, 2011; Ussher et al, 2012). Impaired insulin signaling pathways in cardiomyocytes leads to loss of the major energy source, increased oxidative stress due
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