Up‐regulation of miR‐21 and miR‐23a Contributes to As₂O₃‐induced hERG Channel Deficiency

Abstract

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, knockdown 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-jB, the upstream regulatory factor of miR-21, was significantly up-regulated by As 2 O 3 . This finding revealed that regulation of the NF-jB-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.

Ecological Balance of Oral Microbiota Is Required to Maintain Oral Mesenchymal Stem Cell Homeostasis

“…These gene products play vital roles in many physiological processes, in tissue repair and anti‐inflammatory responses. It has been confirmed that Sp1 is a direct target of miR‐21 in human smooth muscle cells and HEK293 cell lines . These findings collectively suggest that Sp1 may be a candidate target gene of miR‐21 in mouse cells.…”

Salvianolic Acid A Protects H9c2 Cells from Arsenic Trioxide-Induced Injury via Inhibition of the MAPK Signaling Pathway

“…Despite its remarkable effects on certain cancer types, ATO has adverse effects, such as cardiac toxicity; thus, its clinical applications are restricted [24-26]. ATO cardiotoxicity is known to proceed by As 3+ binding to sulfhydryl groups of proteins, thereby damaging the mitochondrial respiratory chain and generating excessive ROS, eventually leading to myocardial cell apoptosis [27, 28].…”

Arsenic trioxide and angiotensin II have inhibitory effects on HERG protein expression: Evidence for the role of PML SUMOylation

“…The therapeutic use of ATO is burdened by broad cardiotoxicity that is characterized by a prolonged QT interval, which can result in life-threatening torsade de pointes and cardiac death. Substantial evidence has been collected demonstrating that ATO can disrupt the HERG current by interfering with trafficking to the cellular membrane, as well as through reduction in HERG protein abundance [ 6 ]. A previous analysis of ATO-induced long QT syndrome revealed that ATO treatment of guinea pigs caused an increase in transforming growth factor β1 (TGF-β1) secretion, while HERG protein expression was decreased [ 7 ].…”