MIR448 antagomir reduces arrhythmic risk after myocardial infarction by upregulating the cardiac sodium channel.

Gyeoung-Jin Kang,Samuel C Dudley,An Xie,Hong Liu

doi:10.1172/jci.insight.140759

Abstract

Cardiac ischemia is associated with arrhythmias; however, effective therapies are currently limited. The cardiac voltage-gated sodium channel α subunit (SCN5A), encoding the Nav1.5 current, plays a key role in the cardiac electrical conduction and arrhythmic risk. Here, we show that hypoxia reduces Nav1.5 through effects on a miR, miR-448. miR-448 expression is increased in ischemic cardiomyopathy. miR-448 has a conserved binding site in 3′-UTR of SCN5A. miR-448 binding to this site suppressed SCN5A expression and sodium currents. Hypoxia-induced HIF-1α and NF-κB were major transcriptional regulators for MIR448. Moreover, hypoxia relieved MIR448 transcriptional suppression by RE1 silencing transcription factor. Therefore, miR-448 inhibition reduced arrhythmic risk after myocardial infarction. Here, we show that ischemia drove miR-448 expression, reduced Nav1.5 current, and increased arrhythmic risk. Arrhythmic risk was improved by preventing Nav1.5 downregulation, suggesting a new approach to antiarrhythmic therapy.

Highlights

Cardiac ischemia is associated with arrhythmic risk; effective therapies are limited
Compared with normoxia (21% O2), incubating with hypoxia (2% O2) for 6 hours caused an increase in the levels of both the mature and precursor form of miR-448 (Figure 1C and Supplemental Figure 1B). miR-448 normoxic levels were comparable to those obtained in vivo under control conditions, and similar changes in miR-448 in response to changes in O2 tension were noted in acutely isolated adult CMs (Supplemental Figure 1C). miR-448 expression was increased by the hypoxia-mimetic chemicals, cobalt chloride (CoCl2), desferrioxamine (DFX), and dimethyloxalylglycine (DMOG) (Figure 1D and Supplemental Figure 1D)
SCN5A alterations, either up- or downregulation, are known to cause arrhythmias, and SCN5A is downregulated in ischemic cardiomyopathy [27,28,29]

Summary

Introduction

Cardiac ischemia is associated with arrhythmic risk; effective therapies are limited. Ischemic cardiomyopathy is associated with reduced Nav1.5, contributing to arrhythmic risk [1,2,3,4]. Previous studies show that the regulation of Nav1.5 expression depends on equilibrium between different mechanisms, such as gene transcription, RNA processing, posttranscriptional regulation by miRNA or RNA-binding proteins, protein synthesis, assembly, and posttranslational modification and trafficking [5,6,7,8]. Cardiac sodium channel downregulation can be mediated by transcriptional regulation, posttranscriptional mRNA splicing, modulation of mRNA stability, translational regulation, and posttranslational modification [9,10,11,12,13,14]. We show that miR-448 is upregulated in cardiac ischemia and contributes to the downregulation of Nav1.5

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Results

Conclusion