[Targeted inhibition of miR-503 upregulates Apelin expression to alleviate myocardial infarction in mice]

To investigate the effect of inhibiting miR-503 on myocardial infarction (MI) and clarify its upstream regulatory factors and downstream effector pathways to identify potential therapeutic targets for MI.

Mouse models of MI established by ligation of the left anterior descending coronary artery were treated with intravenous injections of normal saline, antagomir-503 or antagomiR-NC (n=5). Cardiac function and infarct size of the mice were evaluated by echocardiography and TTC staining, respectively. Primary neonatal rat cardiomyocytes with hypoxic exposure were treated with AMO-503 or its negative control, and the changes in miR-503 expression was detected by qRT-PCR. Cell viability, injury, apoptosis, mitochondrial membrane potential, and ultrastructure were assessed using MTT assay, LDH release assay, TUNEL staining, JC-1 staining, and transmission electron microscopy, respectively. Western blotting was performed to detect the changes in apoptosis-related proteins and the key targets.

MiR-503 expression was significantly upregulated in both MI mouse hearts and hypoxic cardiomyocytes. In MI mouse models, antagomir-503 significantly improved cardiac function, reduced infarct size, downregulated Bax and cleaved caspase-3 expressions, and upregulated Apelin expression. In hypoxic neonatal rat cardiomyocytes, treatment with AMO-503 significantly enhanced cell viability, decreased cell apoptosis rate, and restored mitochondrial membrane potential. Mechanistically, the long non-coding RNA AK134630 could bind to and negatively regulate miR-503, and inhibition of miR-503 effectively relieved the inhibitory effect of RNA AK134630 on the downstream target gene Apelin.

Inhibition of miR-503 alleviates MI injury in mice by upregulating Apelin expression to inhibit cardiomyocyte apoptosis and protect mitochondrial function, and AK134630 participates in this regulatory mechanism as an upstream ceRNA of miR-503.