HuR-mediated SCN5A messenger RNA stability reduces arrhythmic risk in heart failure
Heart rhythm, 2018•Elsevier
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 …
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 …
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.
Elsevier