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 I_Kr and inward rectifier K⁺ current I_K1, 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 I_Kr 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 I_K1. 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.