The muscle-specific microRNA miR-1 regulates cardiac arrhythmogenic potential by targeting GJA1 and KCNJ2.
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.
Yang
Baofeng
B
Department of Pharmacology (State-Province Key Laboratories of Biomedicine-Pharmaceutics of China), Harbin Medical University, Harbin, Heilongjiang 150086, China. yangbf@ems.hrbmu.edu.cn
Lin
Huixian
H
Xiao
Jiening
J
Lu
Yanjie
Y
Luo
Xiaobin
X
Li
Baoxin
B
Zhang
Ying
Y
Xu
Chaoqian
C
Bai
Yunlong
Y
Wang
Huizhen
H
Chen
Guohao
G
Wang
Zhiguo
Z
D000200:Action Potentials / Q000502:physiology*; D000818:Animals; D001145:Arrhythmias, Cardiac / Q000235:genetics / Q000378:metabolism*; D001483:Base Sequence; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000378:metabolism; D018031:Connexin 43 / Q000235:genetics / Q000378:metabolism*; D003324:Coronary Artery Disease / Q000235:genetics / Q000378:metabolism*; D017931:DNA Primers; D004562:Electrocardiography; D005786:Gene Expression Regulation; D006801:Humans; D035683:MicroRNAs / Q000378:metabolism*; D008969:Molecular Sequence Data; D016296:Mutagenesis; D018006:Myogenic Regulatory Factors / Q000378:metabolism; D024661:Potassium Channels, Inwardly Rectifying / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D017422:Sequence Analysis, DNA; D015398:Signal Transduction / Q000502:physiology
D018031:Connexin 43; D017931:DNA Primers; C500216:GJA1 protein, human; C489457:KCNJ2 protein, human; D035683:MicroRNAs; D018006:Myogenic Regulatory Factors; D024661:Potassium Channels, Inwardly Rectifying; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2