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Abstract 11173: Long Non-Coding RNA Linc00667 Modulates Cardiac Sodium Channel Downregulation During Ischemia


 Background:
 The voltage-gated cardiac sodium channel α subunit (
 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. We recently reported that microRNA (miRNA)-448 contributes to the
 SCN5A
 mRNA instability in ischemic conditions.
 
 
 Objective:
 Long intergenic non-protein coding RNA 667 (LINC00667) is expressed in heart and can bind miRNA-448. We investigated the interaction of these two non-coding RNAs (ncRNAs) in regulating
 SCN5A
 .
 
 
 Methods:
 The expressions of
 SCN5A
 , miR-448 and LINC00667 were determined by quantitative real time polymerase chain reaction. The effects of ncRNAs on sodium current were determined in induced pluripotent stem cells-derived cardiomyocytes. The interaction between two ncRNAs was confirmed by pull-down assay.
 
 
 Results:
 LINC00667 has two binding sites for miR-448. A pull-down assay using biotin-tagged miR-448 showed direct binding of LINC00667 to miR-448. This indicates that LINC00667 could act as a competitor through the sponge function to miR-448. The expression of LINC00667 was decreased in human ischemic cardiomyopathy tissues compared to healthy controls. DFX treatment, a hypoxia mimetic chemical, or hypoxic condition (2% O
 2
 ) resulted in reduced LINC00667 and reduced
 SCN5A
 mRNA in cardiomyocyte. Furthermore, LINC00667 inhibition by siRNA or antisense oligo showed reduction of
 SCN5A
 mRNA. This reduction is expected to enhance the effect of miR-448 and is expected to be inhibited by treatment with a DNA construct containing the miR-448 binding site of LINC00667 or "miR-448 sponge".
 
 
 Conclusion:
 SCN5A
 is downregulated by hypoxia. In addition to upregulation of miR-448, which destabilizes
 SCN5A
 mRNA by direct binding, LINC00667 inhibition of miR-448 was relieved by hypoxia increasing the effect of miR-448 on
 SCN5A
 . Therefore, LINC00667 upregulation may represent a method to decrease arrhythmic risk during cardiomyopathy by raising
 SCN5A
 levels.
