Upregulation of microRNA-1 and microRNA-133 contributes to arsenic-induced cardiac electrical remodeling.

Abstract

BACKGROUND: A large body of evidence showed that arsenic trioxide (As(2)O(3)), 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 As(2)O(3)-induced QT prolongation. METHODS: A guinea pig model of As(2)O(3)-induced QT prolongation was established by intravenous injection with As(2)O(3). 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 As(2)O(3). As(2)O(3) induced a significant upregulation of the muscle-specific miR-1 and miR-133, as well as their transactivator serum response factor. As(2)O(3) 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 As(2)O(3). CONCLUSIONS: Deregulation of miR-133 and miR-1 underlies As(2)O(3)-induced cardiac electrical disorders and these miRs may serve as potential therapeutic targets for the handling of As(2)O(3) cardiotoxicity.