Upregulation of microRNA-22 contributes to myocardial ischemia-reperfusion injury by interfering with the mitochondrial function
| Autor: | He Wang, Xiaoyan Zhu, Xiao-Lu Tang, Jiankui Du, Jianqiang Lu, Xin Ni, Binhai Cong, Qing Yu, Chang-Nan Wang, Long Wang |
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| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Pathology medicine.medical_specialty Ischemia Myocardial Reperfusion Injury 030204 cardiovascular system & hematology Mitochondrion Biology Pharmacology Biochemistry 03 medical and health sciences Adenosine Triphosphate 0302 clinical medicine Sirtuin 1 Downregulation and upregulation Superoxides Physiology (medical) medicine Animals Humans Myocytes Cardiac Receptor Creatine Kinase Membrane Potential Mitochondrial chemistry.chemical_classification Reactive oxygen species L-Lactate Dehydrogenase medicine.disease Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha Mitochondria Rats MicroRNAs Oxidative Stress 030104 developmental biology Gene Expression Regulation chemistry Apoptosis biology.protein Creatine kinase Reperfusion injury |
| Zdroj: | Free Radical Biology and Medicine. 96:406-417 |
| ISSN: | 0891-5849 |
| DOI: | 10.1016/j.freeradbiomed.2016.05.006 |
| Popis: | Mitochondrial oxidative damage is critically involved in cardiac ischemia reperfusion (I/R) injury. MicroRNA-22 (miR-22) has been predicted to potentially target sirtuin-1 (Sirt1) and peroxisome proliferator-activated receptor-γ coactivator-1α (PGC1α), both of which are known to provide protection against mitochondrial oxidative injury. The present study aims to investigate whether miR-22 is involved in the regulation of cardiac I/R injury by regulation of mitochondrial function. We found that miR-22 level was significantly increased in rat hearts subjected to I/R injury, as compared with the sham group. Intra-myocardial injection of 20 ug miR-22 inhibitor reduced I/R injury as evidenced by significant decreases in cardiac infarct size, serum lactate dehydrogenase (LDH) and creatine kinase (CK) levels and the number of apoptotic cardiomyocytes. H9c2 cardiomyocytes exposed to hypoxia/reoxygenation (H/R) insult exhibited an increase in miR-22 expression, which was blocked by reactive oxygen species (ROS) scavenger and p53 inhibitor. In addition, miR-22 inhibitor attenuated, whereas miR-22 mimic aggravated H/R-induced injury in H9c2 cardiomyocytes. MiR-22 inhibitor per se had no significant effect on cardiac mitochondrial function. Mitochondria from rat receiving miR-22 inhibitor 48h before ischemia were found to have a significantly less mitochondrial superoxide production and greater mitochondrial membrane potential and ATP production as compared with rat receiving miR control. In H9c2 cardiomyocyte, it was found that miR-22 mimic aggravated, whilst miR-22 inhibitor significantly attenuated H/R-induced mitochondrial damage. By using real time PCR, western blot and dual-luciferase reporter gene analyses, we identified Sirt1 and PGC1α as miR-22 targets in cardiomyocytes. It was found that silencing of Sirt1 abolished the protective effect of miR-22 inhibitor against H/R-induced mitochondrial dysfunction and cell injury in cardiomyocytes. Taken together, our findings reveal a novel molecular mechanism for cardiac mitochondrial dysfunction during myocardial I/R injury at the miRNA level and demonstrate the therapeutic potential of miR-22 inhibition for acute myocardial I/R injury by maintaining cardiac mitochondrial function. |
| Databáze: | OpenAIRE |
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