Acute myocardial infarction is the leading cause of death and disability worldwide. Reperfusion is the main treatment method. However, ischemia-reperfusion (I/R) injury aggravates tissue and cell damage. In this study, we aim to find a strategy to reduce I/R injury and promote cardiac function recovery. The expression of AK003290 was downregulated in I/R injury both in vitro and in vivo. Overexpression of AK003290 reduced infarction area, oxidative stress, cell apoptosis, and promoted cardiac function recovery. AK003290 was observed to sponge miR-539-3p. Moreover, the expression of miR-539-3p was upregulated in I/R injury. Overexpression of miR-539-3p reversed the beneficial role of AK003290 in I/R injury. The target gene of miR-539-3p was proved to be ErbB4, as identified by database prediction, dual-luciferase reporter assay, and pull-down assay. The expression of ErbB4 was negatively correlated with the expression of miR-539-3p, but positively correlated with the expression of AK003290. Subsequently, the key downstream proteins were determined. AK003290 promoted p-AKT and bcl-2 expression and inhibited p-ERK1/2, Bax, cytoplasmic cyto-c, and c-caspase-3 expression. The application of ErbB4 siRNA significantly reversed the effect of AK003290 on the expression of these proteins. These results suggest that ErbB4 is the key downstream gene, which regulates myocardial cell apoptosis by influencing the miR-539-3p expression. To the best of knowledge, this study is the first to demonstrate that the AK003290/miR-539-3p/ErbB4 axis regulates myocardial cell apoptosis. These findings provide a potential novel target for the treatment of myocardial I/R injury.
