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

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

Research output: Contribution to journalArticle

3 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)1072-1080
Number of pages9
JournalHeart Rhythm
Volume15
Issue number7
DOIs
StatePublished - Jul 2018

Fingerprint

RNA Stability
Heart Failure
Messenger RNA
Down-Regulation
Cardiac Myocytes
Virion
Action Potentials
Cardiac Arrhythmias
Injections
RNA-Binding Proteins
Sodium Channels
Reverse Transcriptase Polymerase Chain Reaction
Ion Channels
Real-Time Polymerase Chain Reaction
Sodium
Myocardial Infarction

Keywords

  • Arrhythmia
  • Cardiac sodium channel
  • Heart failure
  • RNA-binding protein
  • mRNA decay

Cite this

HuR-mediated SCN5A messenger RNA stability reduces arrhythmic risk in heart failure. / Zhou, Anyu; Xie, An; Kim, Tae Yun; Liu, Hong; Shi, Guangbin; Kang, Gyeoung Jin; Jiang, Ning; Liu, Man; Jeong, Euy Myoung; Choi, Bum Rak; Dudley, Samuel C.

In: Heart Rhythm, Vol. 15, No. 7, 07.2018, p. 1072-1080.

Research output: Contribution to journalArticle

Zhou, Anyu ; Xie, An ; Kim, Tae Yun ; Liu, Hong ; Shi, Guangbin ; Kang, Gyeoung Jin ; Jiang, Ning ; Liu, Man ; Jeong, Euy Myoung ; Choi, Bum Rak ; Dudley, Samuel C. / HuR-mediated SCN5A messenger RNA stability reduces arrhythmic risk in heart failure. In: Heart Rhythm. 2018 ; Vol. 15, No. 7. pp. 1072-1080.
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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.",
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author = "Anyu Zhou and An Xie and Kim, {Tae Yun} and Hong Liu and Guangbin Shi and Kang, {Gyeoung Jin} and Ning Jiang and Man Liu and Jeong, {Euy Myoung} and Choi, {Bum Rak} and Dudley, {Samuel C.}",
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T1 - HuR-mediated SCN5A messenger RNA stability reduces arrhythmic risk in heart failure

AU - Zhou, Anyu

AU - Xie, An

AU - Kim, Tae Yun

AU - Liu, Hong

AU - Shi, Guangbin

AU - Kang, Gyeoung Jin

AU - Jiang, Ning

AU - Liu, Man

AU - Jeong, Euy Myoung

AU - Choi, Bum Rak

AU - Dudley, Samuel C.

PY - 2018/7

Y1 - 2018/7

N2 - 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.

AB - 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.

KW - Arrhythmia

KW - Cardiac sodium channel

KW - Heart failure

KW - RNA-binding protein

KW - mRNA decay

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