MicroRNA miR-133 Represses HERG K+ Channel Expression Contributing to QT Prolongation in Diabetic Hearts

Jiening Xiao,Xiaobin Luo,Huixian Lin,Ying Zhang,Yanjie Lu,Ning Wang,Yiqiang Zhang,Baofeng Yang,Zhiguo Wang

doi:10.1074/jbc.c700015200

Abstract

We have previously found that the ether-a-go-go related gene (ERG), a long QT syndrome gene encoding a key K(+) channel (I(Kr)) in cardiac cells, is severely depressed in its expression at the protein level but not at the mRNA level in diabetic subjects. The mechanisms underlying the disparate alterations of ERG protein and mRNA, however, remained unknown. We report here a remarkable overexpression of miR-133 in hearts from a rabbit model of diabetes, and in parallel the expression of serum response factor (SRF), which is known to be a transactivator of miR-133, was also robustly increased. Delivery of exogenous miR-133 into the rabbit myocytes and cell lines produced post-transcriptional repression of ERG, down-regulating ERG protein level without altering its transcript level and caused substantial depression of I(Kr), an effect abrogated by the miR-133 antisense inhibitor. Functional inhibition or gene silencing of SRF down-regulated miR-133 expression and increased I(Kr) density. Repression of ERG by miR-133 likely underlies the differential changes of ERG protein and transcript thereby depression of I(Kr), and contributes to repolarization slowing thereby QT prolongation and the associated arrhythmias, in diabetic hearts. Our study provided the first evidence for the pathological role of miR-133 in adult hearts and thus expanded our understanding of the cellular function and pathophysiological roles of miRNAs.

Highlights

MicroRNAs are endogenous ϳ22-nucleotide non-coding RNAs that anneal to inexactly complementary sequences in the 3Ј-untranslated regions of target mRNAs of protein-coding genes to regulate gene expression
We proposed that the muscle-specific miRNAs miR-1/miR133 are able to repress human ethera-go-go-related gene (HERG) translation while keeping its mRNA unaffected and their levels are up-regulated in diabetic hearts, which causes the disparate changes of HERG protein and mRNA levels
We reproduced the observations reported in our previous study [9, 10], i.e. the protein level of the rabbit ether-a-go-go related gene (ERG) was significantly lower in diabetic hearts than in healthy hearts despite that the transcript level remained unchanged

Summary

ACCELERATED PUBLICATION

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EXPERIMENTAL PROCEDURES

RESULTS

DISCUSSION

ADDITIONS AND CORRECTIONS