Department of Cardiology, The Warren Alpert Medical School of Brown University, Providence, Rhode Island.
Department of Cardiology, The Warren Alpert Medical School of Brown University, Providence, Rhode Island; The Lillehei Heart Institute, University of Minnesota, Minneapolis, Minnesota.
Heart Rhythm. 2018 Jul;15(7):1072-1080. doi: 10.1016/j.hrthm.2018.02.018. Epub 2018 Feb 16.
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.
The purpose of this article was to investigate whether HuR regulates SCN5A mRNA expression and whether manipulation of HuR benefits arrhythmia control in HF.
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.
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.
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.
心力衰竭（HF）中钠电流下调与心律失常风险增加有关。信使 RNA（mRNA）稳定蛋白 HuR（也称为 ELAVL1）的表达减少可能是导致钠通道基因 SCN5A mRNA 下调的原因。
本文旨在研究 HuR 是否调节 SCN5A mRNA 的表达，以及 HuR 的操纵是否有益于 HF 中的心律失常控制。
采用定量实时逆转录聚合酶链反应（qRT-PCR）研究 SCN5A 的表达。采用完整心脏光学标测技术研究在心肌梗死和 HF 后注射携带 HuR 的 AAV9 病毒颗粒的小鼠中，HuR 对传导速度和动作电位上升的影响。
HuR 与心肌细胞中的 SCN5A mRNA 相关，并且在衰竭心脏中 HuR 的表达下调。HuR 与 SCN5A mRNA 的结合保护 SCN5A mRNA 免受降解。注射携带 HuR 的 AAV9 病毒颗粒可增加 MI 后小鼠心脏组织中的 SCN5A 表达。完整心脏光学标测显示，HuR 的过表达可改善梗死边缘区的动作电位上升和传导速度，从而降低 MI 后折返性心律失常的风险。
我们的数据表明，HuR 是维持心肌细胞中 SCN5A mRNA 丰度的重要 RNA 结合蛋白。HuR 的表达减少可能至少部分导致缺血性 HF 中 SCN5A mRNA 表达的下调。HuR 的过表达可能挽救 SCN5A 表达的降低，并降低 HF 中的心律失常风险。增加 mRNA 稳定性以增加离子通道电流可能纠正 HF 中的基本缺陷，并代表抗心律失常治疗的新范例。
