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LncRNA MALAT1/Calpain-1 Axis in ATO Induced hERG Channel Deficiency
Caichuan Yan1, Yuexin Li1, Xiaoxu Li1
1Department of Pharmacology, College of Pharmacy, Harbin Medical University, Harbin, People's Republic of China.
Drug Design, Development and Therapy
|March 5, 2025
Summary
Arsenic trioxide (ATO) causes cardiotoxicity by increasing MALAT1, which activates calpain-1 and reduces hERG channels. Tanshinone IIA and fexofenadine counteract this, offering potential treatments for acquired long QT syndrome (acLQTS).
Area of Science:
- Cardiovascular Pharmacology
- Molecular Biology
- Oncology
Background:
- KCNH2 (human ether-à-go-go-related gene) encodes the hERG potassium channel, crucial for cardiac repolarization.
- Acquired long QT syndrome (acLQTS) is a serious side effect of certain drugs, including arsenic trioxide (ATO), used to treat acute promyelocytic leukemia.
- ATO-induced cardiotoxicity can lead to life-threatening arrhythmias like torsade de pointes (TdP).
Purpose of the Study:
- Investigate the role of long noncoding RNA MALAT1 in ATO-induced acLQTS.
- Elucidate the molecular mechanisms underlying ATO's cardiotoxic effects.
- Identify potential therapeutic agents to mitigate ATO-induced cardiotoxicity and target interventions for acLQTS.
Main Methods:
- Gene chip arrays to identify dysregulated long noncoding RNAs (lncRNAs).
- Quantitative qRT-PCR and RNA-binding protein immunoprecipitation (RIP) to analyze lncRNA expression and interactions.
- Western blotting for protein analysis and whole-cell patch-clamp recordings to assess hERG channel function.
Main Results:
- Arsenic trioxide (ATO) significantly upregulated MALAT1 expression in cells expressing the hERG channel.
- MALAT1 was found to interact with calpain-1, inhibiting its degradation and enhancing its activity towards the hERG channel.
- Fexofenadine (FEX) and Tanshinone IIA (TAN) mitigated ATO's effects on the MALAT1/calpain-1 pathway, restoring hERG protein levels.
Conclusions:
- ATO-induced cardiotoxicity and hERG channel reduction are associated with MALAT1 overexpression and enhanced calpain-1 activity.
- Tanshinone IIA and fexofenadine may restore hERG levels by reducing MALAT1 expression and counteracting ATO's effects on the MALAT1/calpain-1 pathway.
- This study reveals a novel regulatory mechanism for ATO-induced acLQTS and identifies MALAT1, calpain-1, and potential therapeutic agents as targets for intervention.
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