Downregulation of Long Non-Coding RNA Kcnq1ot1: An Important Mechanism of Arsenic Trioxide-Induced Long QT Syndrome.

Abstract

BACKGROUND/AIMS:

Arsenic trioxide (ATO) is a known anti-acute promyelocytic leukemia (APL) reagent, whose clinical applications are limited by its serious cardiac toxicity and fatal adverse effects, such as sudden cardiac death resulting from long QT syndrome (LQTS). The mechanisms of cardiac arrhythmia due to ATO exposure still need to be elucidated. Long non-coding RNAs (lncRNAs) are emerging as major regulators of various pathophysiological processes. This study aimed to explore the involvement of lncRNAs in ATO-induced LQTS in vivo and in vitro.

METHODS:

For in vivo experiments, mice were administered ATO through the tail vein. For in vitro experiments, ATO was added to the culture medium of primary cultured neonatal mouse cardiomyocytes. To evaluate the effect of lncRNA Kcnq1ot1, siRNA and lentivirus-shRNA were synthesized to knockdown lncRNA Kcnq1ot1.

RESULTS:

After ATO treatment, the Kcnq1ot1 and Kcnq1 expression levels were down regulated. lncRNA Kcnq1ot1 knockdown prolonged the action potential duration (APD) in vitro and exerted LQTS in vivo. Correspondingly, Kcnq1 expression was decreased after silencing lncRNA Kcnq1ot1. However, the knockdown of Kcnq1 exerted no effect on lncRNA Kcnq1ot1 expression.

CONCLUSIONS:

To our knowledge, this report is the first to demonstrate that lncRNA Kcnq1ot1 downregulation is responsible for QT interval prolongation induced by ATO at least partially by repressing Kcnq1 expression. lncRNA Kcnq1ot1 has important pathophysiological functions in the heart and could become a novel antiarrhythmic target.

• Authors: Yanan Jiang, Weijie Du, Qun Chu, Ying Qin, Gulnara Tuguzbaeva, Hui Wang, Anqi Li, Guiyang Li, Yanyao Li, Lu Chai, Er Yue, Xi Sun, Zhiguo Wang, Valentin Pavlov, Baofeng Yang, Yunlong Bai
• Journal: Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology (Cell Physiol Biochem) Vol. 45 Issue 1 Pg. 192-202 ( 2018) ISSN: 1421-9778 [Electronic] Germany
• PMID: 29339628 (Publication Type: Journal Article)
• Copyright: © 2018 The Author(s). Published by S. Karger AG, Basel.

Chemical References

• Arsenicals
• KCNQ1 Potassium Channel
• KCNQ1OT1 RNA
• Kcnq1 protein, mouse
• Oxides
• RNA, Long Noncoding
• RNA, Small Interfering
• Arsenic Trioxide

Topics

• Action Potentials
• Animals
• Arsenic Trioxide
• Arsenicals
• Cells, Cultured
• Down-Regulation
• KCNQ1 Potassium Channel (antagonists & inhibitors, genetics, metabolism)
• Lentivirus (genetics)
• Long QT Syndrome (chemically induced, pathology)
• Mice
• Myocytes, Cardiac (cytology, drug effects, metabolism)
• Oxides (toxicity)
• Patch-Clamp Techniques
• Phenotype
• RNA Interference
• RNA, Long Noncoding (antagonists & inhibitors, genetics, metabolism)
• RNA, Small Interfering (metabolism)