Abstract
BackgroundMyocardial ischaemia reperfusion injury (MIRI) is a difficult problem in clinical practice, and it may involve various microRNAs. This study investigated the role that endogenous microRNA-146a plays in myocardial ischaemia reperfusion and explored the possible target genes.MethodsMIRI models were established in microRNA-146a deficient (KO) and wild type (WT) mice. MicroRNA-146a expression was evaluated in the myocardium of WT mice after reperfusion. The heart function, area of myocardium infarction and in situ apoptosis were compared between the KO and WT mice. Microarray was used to explore possible target genes of microRNA-146a, while qRT-PCR and dual luciferase reporter assays were used for verification. Western blotting was performed to detect the expression levels of the target gene and related signalling molecules. A rescue study was used for further testing.ResultsMicroRNA-146a was upregulated 1 h after reperfusion. MicroRNA-146a deficiency decreased heart function and increased myocardial infarction and apoptosis. Microarray detected 19 apoptosis genes upregulated in the KO mice compared with the WT mice. qRT-PCR and dual luciferase verified that Med1 was one target gene of microRNA-146a. TRAP220, encoded by Med1 in the KO mice, was upregulated, accompanied by an amplified ratio of Bax/Bcl2 and increased cleaved caspase-3. Inhibition of microRNA-146a in H9C2 cells caused increased TRAP220 expression and more apoptosis under the stimulus of hypoxia and re-oxygenation, while knockdown of the increased TRAP220 expression led to decreased cell apoptosis.ConclusionsMicroRNA-146a exerts a protective effect against MIRI, which might be partially mediated by the target gene Med1 and related to the apoptosis signalling pathway.
Highlights
Myocardial ischaemia reperfusion injury (MIRI) is a difficult problem in clinical practice, and it may involve various microRNAs
MicroRNA-146a deficiency increased MIRI MicroRNA-146a deficiency reduced cardiac function in MIRI To explicate the function of endogenous microRNA-146a in MIRI, we built the MIRI model in vivo with microRNA-146a deficient (KO) mice and wild type (WT) mice, and examined cardiac function using echocardiography at the first and third day after reperfusion
The MicroRNA-146a deficiency increased myocardial infarct size in MIRI We checked the infarct and risk size of myocardium after ischaemia reperfusion in KO mice compared with WT mice
Summary
Myocardial ischaemia reperfusion injury (MIRI) is a difficult problem in clinical practice, and it may involve various microRNAs. This study investigated the role that endogenous microRNA-146a plays in myocardial ischaemia reperfusion and explored the possible target genes. Myocardial ischaemia reperfusion injury (MIRI) is a double-edged sword for myocardial infarction patients [1, 2]. In vivo study has shown that inhibition of increased microRNA-24 in the infarction area can alleviate MIRI by preventing the apoptosis of cardiomyocytes [5, 6], whereas injection of exogenous MicroRNA-24 analogues inhibited cardiomyocyte apoptosis, thereby reducing myocardial infarct size and cardiac dysfunction [5, 7, 8]. MicroRNA-21 and microRNA-29 play dual roles in MIRI [4, 5, 9, 10]
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