miR-503 inhibition via antagomir-503 improves cardiac function and reduces infarct size in MI mice

Myocardial infarction (MI) remains a leading cause of morbidity and mortality, characterized by irreversible cardiomyocyte death and subsequent cardiac dysfunction. Current therapies often fall short in fully restoring cardiac function or preventing adverse remodeling. MicroRNAs (miRNAs) are emerging as critical regulators in cardiac pathology, offering novel therapeutic avenues. Specifically, miR-503 has been implicated in various cardiovascular diseases, but its precise role and upstream/downstream regulatory networks in MI were not fully elucidated, presenting a gap for targeted intervention.

Researchers established MI mouse models by ligating the left anterior descending coronary artery. Mice were intravenously injected with antagomir-503 or a negative control (antagomiR-NC), with n=5 mice per group. Cardiac function was assessed via echocardiography, and infarct size by TTC staining. In parallel, primary neonatal rat cardiomyocytes were exposed to hypoxia and treated with AMO-503 or its negative control. qRT-PCR detected miR-503 expression, while MTT assay, LDH release assay, TUNEL staining, JC-1 staining, and transmission electron microscopy evaluated cell viability, injury, apoptosis, mitochondrial membrane potential, and ultrastructure, respectively. Western blotting identified changes in apoptosis-related proteins and key targets.

Expression of miR-503 was significantly upregulated in both MI mouse hearts and hypoxic cardiomyocytes. In the MI mouse models, antagomir-503 treatment significantly improved cardiac function and reduced infarct size. This intervention also downregulated the pro-apoptotic proteins Bax and cleaved caspase-3 expressions, while notably upregulating 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 was found to bind to and negatively regulate miR-503. > Inhibition of miR-503 effectively relieved the inhibitory effect of AK134630 on its downstream target gene, Apelin, demonstrating a crucial regulatory axis. These findings collectively highlight miR-503 as a key player in MI pathology.