Upregulation of microRNA-1 and microRNA-133 contributes to arsenic-induced cardiac electrical remodeling.
BACKGROUND
A large body of evidence showed that arsenic trioxide (As2O3), a front-line drug for the treatment of acute promyelocytic leukemia, induced abnormal cardiac QT prolongation, which hampers its clinical use. The molecular mechanisms for this cardiotoxicity remained unclear. This study aimed to elucidate whether microRNAs (miRs) participate in As2O3-induced QT prolongation.


METHODS
A guinea pig model of As2O3-induced QT prolongation was established by intravenous injection with As2O3. Real-time PCR and Western blot were employed to determine the expression alterations of miRs and mRNAs, and their corresponding proteins.


RESULTS
The QT interval and QRS complex were significantly prolonged in a dose-dependent fashion after 7-day administration of As2O3. As2O3 induced a significant upregulation of the muscle-specific miR-1 and miR-133, as well as their transactivator serum response factor. As2O3 depressed the protein levels of ether-a-go-go related gene (ERG) and Kir2.1, the K(+) channel subunits responsible for delayed rectifier K(+) current IKr and inward rectifier K(+) current IK1, respectively. In vivo transfer of miR-133 by direct intramuscular injection prolonged QTc interval and increased mortality rate, along with depression of ERG protein and IKr in guinea pig hearts. Similarly, forced expression of miR-1 widened QTc interval and QRS complex and increased mortality rate, accompanied by downregulation of Kir2.1 protein and IK1. Application of antisense inhibitors to knockdown miR-1 and miR-133 abolished the cardiac electrical disorders caused by As2O3.


CONCLUSIONS
Deregulation of miR-133 and miR-1 underlies As2O3-induced cardiac electrical disorders and these miRs may serve as potential therapeutic targets for the handling of As2O3 cardiotoxicity.
Department of Pharmacology, The State-Province Key Laboratories of Biomedicine- Pharmaceutics of China, Harbin Medical University, Harbin, Heilongjiang 150081, PR China.
Hongli
H
Shan
Yong
Y
Zhang
Benzhi
B
Cai
Xi
X
Chen
Yuhua
Y
Fan
Lili
L
Yang
Xichuang
X
Chen
Haihai
H
Liang
Ying
Y
Zhang
Xiaohui
X
Song
Chaoqian
C
Xu
Yanjie
Y
Lu
Baofeng
B
Yang
Zhimin
Z
Du
D000818:Animals; D000077237:Arsenic Trioxide; D001152:Arsenicals; D064752:Atrial Remodeling / Q000187:drug effects* / Q000502:physiology; D002478:Cells, Cultured; D006168:Guinea Pigs; D008133:Long QT Syndrome / Q000139:chemically induced / Q000378:metabolism* / Q000503:physiopathology; D008297:Male; D035683:MicroRNAs / Q000096:biosynthesis*; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000502:physiology; D010087:Oxides / Q000633:toxicity*; D015854:Up-Regulation / Q000187:drug effects* / Q000502:physiology
D001152:Arsenicals; C544547:MIRN1 microRNA, human; D035683:MicroRNAs; C517732:Mirn133 microRNA, mouse; D010087:Oxides; D000077237:Arsenic Trioxide