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

Background Downregulated sodium currents in heart failure (HF) have been linked to increased arrhythmic risk. Reduced expression of the messenger RNA (mRNA)–stabilizing protein ELAVL1/HuR 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 myocardial infarct (MI) HF mice after AAV-HuR injection. 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 risks forming reentrant arrhythmia in 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 arrhythmia 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.