Abstract 893: MicroRNA-448 Regulates the Cardiac Sodium Channel During Ischemia

Abstract

Background: The cardiac voltage-gated sodium channel ( SCN5A ; encoding Na v 1.5) plays a key role in cardiac conduction. The sodium channel is downregulated in cardiomyopathy, contributing to arrhythmic risk. In part, this downregulation is because of abnormal mRNA splicing and reduced mRNA stability. The reason for decreased mRNA stability is unclear, however. Objective: Here, we examined whether microRNA-448 (miR-448)can contribute to SCN5A mRNA instability. Methods: Datasets from the Gene Expression Omnibus database were utilized to screen miR-448 in human and mouse heart tissues. The relationship between SCN5A and miR-448 was predicted by three independent prediction tools. The expressions of SCN5A and miR-448 were determined by quantitative real time polymerase chain reaction. Protein levels of Na v 1.5 were determined by Western blot. The effect of miR-448 mimic on sodium current was determined in induced pluripotent stem cells-derived cardiomyocytes. Mouse myocardial infarction was created by left anterior descending coronary artery ligation. Results: The expression of miR-448 is increased in stressed heart after myocardial infarction. The binding sequence for miR-448 is well-conserved in 3’-UTR of SCN5A and miR-448 directly bound to a consensus cis element, suppressing SCN5A expression and sodium currents. miR-448 expression wass increased by hypoxia. Activated by hypoxia, HIF1α and NF-κB activated were major transcriptional regulator for MIR448 . Conclusion: These results indicated that miR-448 contributed to post-transcriptional modification of SCN5A . miR-448 is likely one cause of sodium channel downregulation during ischemia and may represent a target for antagomir therapy to reduce arrhythmic risk associated with cardiomyopathy.. Keywords: SCN5A, miR-448, Cardiomyocyte, Hypoxia, NF-κB, HIF1α