HuR-mediated SCN5A messenger RNA stability reduces arrhythmic risk in heart failure.

Abstract

BACKGROUND:

Downregulated sodium currents in heart failure (HF) have been linked to increased arrhythmic risk. Reduced expression of the messenger RNA (mRNA)-stabilizing protein HuR (also known as ELAVL1) may be responsible for the downregulation of sodium channel gene SCN5A mRNA.

OBJECTIVE:

The purpose of this article was to investigate whether HuR regulates SCN5A mRNA expression and whether manipulation of HuR benefits arrhythmia control in HF.

METHODS:

Quantitative real-time reverse-transcriptase polymerase chain reaction was used to investigate the expression of SCN5A. Optical mapping of the intact heart was adopted to study the effects of HuR on the conduction velocity and action potential upstroke in mice with myocardial infarct and HF after injection of AAV9 viral particles carrying HuR.

RESULTS:

HuR was associated with SCN5A mRNA in cardiomyocytes, and expression of HuR was downregulated in failing hearts. The association of HuR and SCN5A mRNA protected SCN5A mRNA from decay. Injection of AAV9 viral particles carrying HuR increased SCN5A expression in mouse heart tissues after MI. Optical mapping of the intact heart demonstrated that overexpression of HuR improved action potential upstroke and conduction velocity in the infarct border zone, which reduced the risk of reentrant arrhythmia after MI.

CONCLUSION:

Our data indicate that HuR is an important RNA-binding protein in maintaining SCN5A mRNA abundance in cardiomyocytes. Reduced expression of HuR may be at least partially responsible for the downregulation of SCN5A mRNA expression in ischemic HF. Overexpression of HuR may rescue decreased SCN5A expression and reduce arrhythmic risk in HF. Increasing mRNA stability to increase ion channel currents may correct a fundamental defect in HF and represent a new paradigm in antiarrhythmic therapy.

• Authors: Anyu Zhou, An Xie, Tae Yun Kim, Hong Liu, Guangbin Shi, Gyeoung-Jin Kang, Ning Jiang, Man Liu, Euy-Myoung Jeong, Bum-Rak Choi, Samuel C Dudley Jr
• Journal: Heart rhythm (Heart Rhythm) Vol. 15 Issue 7 Pg. 1072-1080 (07 2018) ISSN: 1556-3871 [Electronic] United States
• PMID: 29454929 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: Copyright © 2018 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.

Chemical References

• ELAV-Like Protein 1
• ELAVL1 protein, human
• NAV1.5 Voltage-Gated Sodium Channel
• RNA, Messenger
• SCN5A protein, human

Topics

• Animals
• Arrhythmias, Cardiac (etiology, genetics, pathology)
• Cells, Cultured
• ELAV-Like Protein 1 (biosynthesis, genetics)
• Gene Expression Regulation
• Heart Failure (complications, genetics, metabolism)
• Humans
• Male
• Mice
• Mice, Inbred C57BL
• Myocardium (metabolism, pathology)
• NAV1.5 Voltage-Gated Sodium Channel (biosynthesis, genetics)
• RNA, Messenger (genetics)
• Reverse Transcriptase Polymerase Chain Reaction