MicroRNA miR-133 represses HERG K+ channel expression contributing to QT prolongation in diabetic hearts.
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.
Xiao
Jiening
J
Research Center, Montreal Heart Institute, Montreal, Quebec H1T 1C8, Canada.
Luo
Xiaobin
X
Lin
Huixian
H
Zhang
Ying
Y
Lu
Yanjie
Y
Wang
Ning
N
Zhang
Yiqiang
Y
Yang
Baofeng
B
Wang
Zhiguo
Z
D000818:Animals; D003921:Diabetes Mellitus, Experimental / Q000150:complications / Q000378:metabolism*; D015536:Down-Regulation; D051638:Ether-A-Go-Go Potassium Channels / Q000096:biosynthesis*; D008133:Long QT Syndrome / Q000209:etiology / Q000378:metabolism*; D008297:Male; D008564:Membrane Potentials; D035683:MicroRNAs / Q000096:biosynthesis*; D009206:Myocardium / Q000378:metabolism*; D011817:Rabbits; D026362:Serum Response Factor / Q000378:metabolism; D014158:Transcription, Genetic; D015533:Transcriptional Activation
D051638:Ether-A-Go-Go Potassium Channels; D035683:MicroRNAs; D026362:Serum Response Factor