Cardioprotective effects of microRNA-18a on acute myocardial infarction by promoting cardiomyocyte autophagy and suppressing cellular senescence via brain derived neurotrophic factor

BACKGROUND: The prevention of cardiovascular diseases is a matter of great concern, of which acute myocardial infarction (AMI) remains one of the leading causes of death resulting in high morbidity worldwide. Emerging evidence highlights the importance of microRNAs (miRNAs) as functional regulators in cardiovascular disease. In this study, an AMI rat model was established in order to investigate the effect of miR-18a on cardiomyocyte autophagy and senescence in AMI and the underlying mechanism. METHODS: In the present study, an AMI model was induced by ligating the anterior descending branch of left coronary artery in Wistar rats. Dual-luciferase reporter gene assay was introduced for exploration on the relationship between miR-18a and brain derived neurotrophic factor (BDNF). The gain- and loss-of-function experiments were performed to elucidate miR-18a and BDNF effects on cell autophagy and senescence in AMI by transfecting hypoxia-exposed H9c2 cells with miR-18a inhibitor or mimic, siRNA against BDNF, or hypoxia-exposed H9c2 cell treatment with an agonist of the Akt/mTOR axis (LM22B-10). RESULTS: Upregulation of miR-18a was found in AMI, while downregulation was present in BDNF to activate the Akt/mTOR axis. Compared with the miR-18a inhibitor group, the expression of p-Akt and p-mTOR increased and the number of senescent cells increased in the miR-18a inhibitor + LM22B-10 group, and the expression of Beclin1, LC3-II, p62 decreased and autophagy decreased (all p < 0.05). Furthermore, this could be rescued by knocking down BDNF or Akt/mTOR axis activation by LM22B-10. CONCLUSION: All in all, downregulation of miR-18a could promote BDNF expression, which offers protection against AMI by inactivating the Akt/mTOR axis, highlighting a promising therapeutic strategy for AMI treatment.