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J. Biol. Chem., Vol. 282, Issue 17, 12363-12367, April 27, 2007

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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^¶||1, and Zhiguo Wang^¶2

From the Research Center, Montreal Heart Institute, Montreal, Quebec H1T 1C8, Canada, the Department of Medicine, University of Montreal, Montreal, Quebec H3C 3J7, Canada, the ^||Department of Pharmacology (State-Province Key Laboratories of Biomedicine-Pharmaceutics), and the ^¶Institute of Cardiovascular Research, Harbin Medical University, Harbin, Heilongjiang 150086, China

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.

Received for publication, January 19, 2007

^* This work was supported in part by the Canada Diabetes Association and Fonds de la Recherche de l'Institut de Cardiologie de Montreal (awarded to Z. W.) and by the National Nature Science Foundation of China (30430780) and the Foundation of National Department of Science and Technology of China (2004CCA06700) (both awarded to B. Y.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Experimental Procedures, Refs. 1–5, and Figs. 1–3.

¹ To whom correspondence may be addressed: Harbin Medical University, Heilongjiang 150086, China. Tel.: 86-451-8667-9473; E-mail: yangbf{at}ems.hrbmu.edu.cn. ² Senior research scholar of the Fonds de Recherche en Sante de Quebec. To whom correspondence may be addressed: Research Center, Montreal Heart Institute, 5000 Belanger East, Montreal, Quebec H1T 1C8, Canada. Tel.: 514-376-3330; Fax: 514-376-1335; E-mail: wz.E-mail:{at}gmail.com.

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