Targeting mir128-3p alleviates myocardial insulin resistance and prevents ischemia-induced heart failure
| Autor: | Oliver J. Müller, Elizabeth J. Cartwright, Lucy Collins, Norbert Frey, Wei Liu, Binh Yen Nguyen, Pablo Binder, Min Zi, Karolina Sekeres, Tayyiba Azam, Xin Wang, Juwei Jiang, Namrita Kaur, Fay Pu, Kaomei Guan, Susanne Hille, Andrea Ruiz-Velasco, Han Xiao |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
medicine.medical_specialty IRS1 QH301-705.5 medicine.medical_treatment Science Ischemia 030204 cardiovascular system & hematology General Biochemistry Genetics and Molecular Biology 03 medical and health sciences 0302 clinical medicine Insulin resistance Internal medicine medicine Myocardial infarction Biology (General) miRNA Cardioprotection General Immunology and Microbiology business.industry General Neuroscience Insulin General Medicine Hypoxia (medical) medicine.disease cardiac insulin resistance 030104 developmental biology Endocrinology myocardial infarction Heart failure cardioprotection Medicine medicine.symptom business |
| Zdroj: | eLife, Vol 9 (2020) |
| 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. |
| Databáze: | OpenAIRE |
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