MicroRNA-146a protects against myocardial ischaemia reperfusion injury by targeting Med1

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.

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“…However, OI could significantly diminish ROS accumulation and cell death induced by CCl4 in vitro ( Figures 4A,C,G ). Cleaved PARP and caspase 3 are important markers of cell apoptosis ( Zhang et al, 2019 ). In our study, cleaved PARP and caspase 3 were evaluated by immunoblot, and we found that CCl4 elevated them in NCTC 1469 cells, while OI treatment could decrease their expression.…”

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“…73 Another study in miR-146a À/À mice revealed that miR-146a deficiency increased infarct size and apoptosis after I/R injury through the upregulation of 19 apoptosis-related genes such as mediator complex subunit 1 (Med1). 74 On the other hand, tyrosine kinases inhibitors agents such as sunitinib (SNT), beyond their beneficial effects on cancer, have shown adverse effects on the cardiovascular system. 75 Interestingly, Shen et al showed a significant downregulation of miR-146a in the myocardium of SNT-treated mice.…”