Up-regulation of miR-21 and miR-23a Contributes to As2 O3 -induced hERG Channel Deficiency.
Arsenic trioxide (As2O3) is used to treat acute pro-myelocytic leukaemia. However, the cardiotoxicity of long QT syndrome restricts its clinical application. Previous studies showed that As2O3 can damage the hERG current via disturbing its trafficking to cellular membrane. Consistent with these findings, in this study, we reported that As2O3 inhibited hERG channel at both protein and mRNA levels and damaged hERG current but did not affect channel kinetics. Further, we demonstrated that As2O3 up-regulated miR-21 and miR-23a expression in hERG-HEK293 cells and neonatal cardiomyocytes. In addition, knock-down of miR-21 by its specific antisense molecules AMO-21 was able to rescue Sp1 and hERG inhibition caused by As2O3. Consistently, phosphorylation of NF-κB, the upstream regulatory factor of miR-21, was significantly up-regulated by As2O3 . This finding revealed that regulation of the NF-κB-miR-21-Sp1 signalling pathway is a novel mechanism for As2O3-induced hERG inhibition. Meanwhile, the expression of Hsp90 and hERG was rescued by transfection with AMO-23a. And the hERG channel inhibition induced by As2O3 was rescued after being transfected with AMO-23a, which may be a molecular mechanism for the role of As2O3 in hERG trafficking deficiency. In brief, our study revealed that miR-21 and miR-23a are involved in As2O3-induced hERG deficiency at transcriptional and transportational levels. This discovery may provide a novel mechanism of As2O3-induced hERG channel deficiency, and these miRNAs may serve as potential therapeutic targets for the handling of As2O3 cardiotoxicity.
Department of Pharmacology, Harbin Medical University, Harbin, China.
Xin
X
Zhao
Yuan-Qi
YQ
Shi
Cai-Chuan
CC
Yan
Pan-feng
PF
Feng
Xue
X
Wang
Rui
R
Zhang
Xiao
X
Zhang
Bao-Xin
BX
Li
D000818:Animals; D000831:Animals, Newborn; D000077237:Arsenic Trioxide; D001152:Arsenicals; D051638:Ether-A-Go-Go Potassium Channels / Q000172:deficiency* / Q000187:drug effects; D066298:In Vitro Techniques; D007700:Kinetics; D035683:MicroRNAs / Q000096:biosynthesis* / Q000187:drug effects; D032383:Myocytes, Cardiac / Q000187:drug effects; D016328:NF-kappa B / Q000378:metabolism; D010087:Oxides / Q000633:toxicity*; D010766:Phosphorylation; D026902:Potassium Channel Blockers / Q000633:toxicity*; D051381:Rats; D017207:Rats, Sprague-Dawley; D014162:Transfection; D015854:Up-Regulation / Q000187:drug effects
D000077237:Arsenic Trioxide; D001152:Arsenicals; D051638:Ether-A-Go-Go Potassium Channels; D035683:MicroRNAs; D016328:NF-kappa B; D010087:Oxides; D026902:Potassium Channel Blockers; C496886:Kcnh1 protein, rat; C000590974:MIRN23a microRNA, rat; C546082:mirn21 microRNA, rat