MIR448 antagomir reduces arrhythmic risk after myocardial infarction by upregulating the cardiac sodium channel
Gyeoung-Jin Kang, An Xie, Hong Liu, Samuel C. Dudley Jr.
Gyeoung-Jin Kang, An Xie, Hong Liu, Samuel C. Dudley Jr.
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Research Article Cardiology

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

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.

Authors

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

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Figure 5

SCN5A is regulated by hypoxia-induced miR-448.

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SCN5A is regulated by hypoxia-induced miR-448. (A) Diagram of luciferas...
(A) Diagram of luciferase reporter constructs. The miR-448 binding sequences were inserted downstream of the luciferase gene of the pGL3-promoter vector. Cells were transfected with miR-448 decoy and then luciferase (LUC) expression was checked in the presence or absence of DFX. (B) Effect of miR-448 decoy on SCN5A mRNA expression reduced by simulated hypoxia in CMs. Cells were transfected with miR-448 decoy and then stimulated with DFX for 6 hours. (C) Effect of miR-448 decoy on the DFX-induced Nav1.5 protein in CMs. Cells were transfected with miR-448 decoy and then stimulated with DFX for 24 hours. Representative Western blots (top) and bar graph (bottom) representing the quantitative Western blot analysis of Nav1.5. Data are represented as the mean + SD of 3–4 independent experiments. *P < 0.05, ***P < 0.001 (when compared between indicated groups by Student’s t test or 1-way ANOVA with Dunnett’s multiple-comparison test).