Caichuan Yan,* Yuexin Li,* Xiaoxu Li, Yang Li, Yuhao Zhang, Jinyang Sun, Qirui Ding, Xin Zhao, Baoxin Li

Department of Pharmacology, College of Pharmacy, Harbin Medical University, Harbin, People’s Republic of China

*These authors contributed equally to this work

Correspondence: Baoxin Li; Xin Zhao, Department of Pharmacology, College of Pharmacy, Harbin Medical University, Xuefu Road 194, Harbin, Heilongjiang, 150081, People’s Republic of China, Email libaoxin@ems.hrbmu.edu.cn; xin182048739@sina.com

Background: KCNH2 encodes the hERG potassium channel, which is associated with drug-induced long QT syndrome. Arsenic trioxide (ATO) is an effective therapeutic agent for acute promyelocytic leukemia; however, its long-term use can lead to cardiotoxicity, particularly in cases of acquired long QT syndrome (acLQTS), which may result in torsade de pointes (TdP). Therefore, it is essential to comprehend the mechanisms behind acLQTS and to develop effective preventive and therapeutic strategies.
Aim: This study sought to investigate the role and molecular mechanism of MALAT1 in ATO-induced acLQTS. Furthermore, it sought to identify pharmacological agents that could mitigate the cardiotoxic effects of ATO and establish viable intervention targets for the prevention and management of acLQTS.
Methods: First, we employed gene chip arrays to identify target long noncoding RNAs (lncRNAs). Subsequently, we performed quantitative qRT-PCR and RNA-binding protein immunoprecipitation (RIP) to assess lncRNA levels. Next, we utilized Western blotting for protein expression analysis, and finally, we conducted whole-cell patch-clamp recordings to evaluate hERG currents.
Results: Our results revealed a significant upregulation of lncRNA MALAT1 expression in HEK293-hERG cells treated with ATO. Mechanistically, MALAT1 interacts with calpain-1, inhibiting its ubiquitin-mediated degradation and enhancing the cleavage activity of calpain-1 on the hERG channel. FEX and TAN were found to mitigate the effects of ATO on the MALAT1/calpain-1 pathway, ultimately restoring hERG protein levels.
Conclusion: This study demonstrated that ATO-induced enhancement of calpain-1 and reduction of hERG may be linked to the aberrant overexpression of lncRNA MALAT1. Tanshinone IIA and fexofenadine restored the hERG protein levels potentially by decreasing MALAT1 expression and counteracting ATO’s effects on the MALAT1/calpain-1 pathway. Collectively, our research uncovers a previously unreported regulatory mechanism underlying ATO-induced acLQTS. Moreover, it identifies potential molecular targets and intervention strategies for acLQTS therapy.

Keywords: hERG, MALAT1, calpain-1, ATO, LQTS