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Up‐regulation of miR‐21 and miR‐23a Contributes to As 2 O 3 ‐induced hERG Channel Deficiency
Author(s) -
Zhao Xin,
Shi YuanQi,
Yan CaiChuan,
Feng Panfeng,
Wang Xue,
Zhang Rui,
Zhang Xiao,
Li BaoXin
Publication year - 2015
Publication title -
basic and clinical pharmacology and toxicology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.805
H-Index - 90
eISSN - 1742-7843
pISSN - 1742-7835
DOI - 10.1111/bcpt.12348
Subject(s) - herg , arsenic trioxide , transfection , chemistry , microrna , cardiotoxicity , microbiology and biotechnology , hek 293 cells , pharmacology , long qt syndrome , biology , medicine , potassium channel , biochemistry , gene , apoptosis , toxicity , biophysics , organic chemistry , qt interval
Arsenic trioxide (As 2 O 3 ) is used to treat acute pro‐myelocytic leukaemia. However, the cardiotoxicity of long QT syndrome restricts its clinical application. Previous studies showed that As 2 O 3 can damage the hERG current via disturbing its trafficking to cellular membrane. Consistent with these findings, in this study, we reported that As 2 O 3 inhibited hERG channel at both protein and mRNA levels and damaged hERG current but did not affect channel kinetics. Further, we demonstrated that As 2 O 3 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 As 2 O 3 . Consistently, phosphorylation of NF‐κB, the upstream regulatory factor of miR‐21, was significantly up‐regulated by As 2 O 3 . This finding revealed that regulation of the NF‐κB‐miR‐21‐Sp1 signalling pathway is a novel mechanism for As 2 O 3 ‐induced hERG inhibition. Meanwhile, the expression of Hsp90 and hERG was rescued by transfection with AMO‐23a. And the hERG channel inhibition induced by As 2 O 3 was rescued after being transfected with AMO‐23a, which may be a molecular mechanism for the role of As 2 O 3 in hERG trafficking deficiency. In brief, our study revealed that miR‐21 and miR‐23a are involved in As 2 O 3 ‐induced hERG deficiency at transcriptional and transportational levels. This discovery may provide a novel mechanism of As 2 O 3 ‐induced hERG channel deficiency, and these miRNAs may serve as potential therapeutic targets for the handling of As 2 O 3 cardiotoxicity.