MicroRNAs (miRNAs) are endogenous noncoding RNAs, about 22 nucleotides in length, that mediate post-transcriptional gene silencing by annealing to inexactly complementary sequences in the 3'-untranslated regions of target mRNAs. Our current understanding of the functions of miRNAs relies mainly on their tissue-specific or developmental stage-dependent expression and their evolutionary conservation, and therefore is primarily limited to their involvement in developmental regulation and oncogenesis. Of more than 300 miRNAs that have been identified, miR-1 and miR-133 are considered to be muscle specific. Here we show that miR-1 is overexpressed in individuals with coronary artery disease, and that when overexpressed in normal or infarcted rat hearts, it exacerbates arrhythmogenesis. Elimination of miR-1 by an antisense inhibitor in infarcted rat hearts relieved arrhythmogenesis. miR-1 overexpression slowed conduction and depolarized the cytoplasmic membrane by post-transcriptionally repressing KCNJ2 (which encodes the K(+) channel subunit Kir2.1) and GJA1 (which encodes connexin 43), and this likely accounts at least in part for its arrhythmogenic potential. Thus, miR-1 may have important pathophysiological functions in the heart, and is a potential antiarrhythmic target.

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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 posttranscriptional 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.Abnormal QT interval prolongation is a prominent electrical disorder and has been proposed a predictor of mortality in patients with diabetes mellitus (DM), 3 presumably because it is associated with an increased risk of sudden cardiac death consequent to lethal ventricular arrhythmias (1-8). Our recent study revealed that the long QT syndrome gene, human ethera-go-go-related gene (HERG) encoding the channel responsible for rapid delayed rectifier K ϩ current (I Kr ), is significantly down-regulated in its expression in diabetic hearts and this down-regulation contributes critically to diabetic repolarization slowing and QT prolongation (9, 10). Strikingly, HERG expressions at transcriptional and post-transcriptional levels diverge in diabetic hearts, with its protein levels being reduced by some 60% while the mRNA levels remaining essentially unaltered (10). These disparate changes indicate that HERG expression is impaired mainly at the post-transcriptional level; however, it remained unclear what are the determinants for the differential regulations of HERG expression at protein and transcript levels.MicroRNAs (miRNAs) 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. The major characteristics of miRNA actions is to specify translational repression without affecting the levels of the targeted mRNA (11, 12). Among Ͼ300 miRNAs identified thus far, miR-1 and miR-133 are known to specifically express in adult cardiac and skeletal muscle tissues (13,14). Recent stud...