Regulation and role of the cardiac sodium channel Nav1.5 in heart failure

心脏钠通道 Nav1.5 在心力衰竭中的调节和作用

• 批准号: 10544732
• 负责人: RYAN L BOUDREAU
• 金额: $ 38.63万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-01-10 至 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10544732
• 关键词: Action Potentials; Aging; Anabolism; Arrhythmia; Binding Sites; Bioinformatics; Biology; Cardiac; Cardiac Myocytes; Cardiac health; Cardiomyopathies; Caring; Cessation of life; Clinical; Code; Data; Dilated Cardiomyopathy; Disease; Electrocardiogram; Electrophysiology (science); Exhibits; Fibrosis; Foundations; Future; Gene Expression; Goals; Grant; Healthcare Systems; Heart; Heart Diseases; Heart Rate; Heart failure; Heterozygote; Human; Inherited; Investigation; Ion Channel; Ions; Ischemia; Knock-out; Knockout Mice; Knowledge; Link; Measures; Messenger RNA; Metabolic; Metabolic stress; Metabolism; MicroRNAs; Mitochondria; Morbidity - disease rate; Mus; Mutation; NADPH Oxidase; Operative Surgical Procedures; Outcome; Oxidation-Reduction; Oxidative Stress; Pathogenicity; Pathology; Pathway interactions; Patients; Predisposing Factor; Predisposition; Prevalence; Public Health; Publishing; RNA; RNA-Binding Proteins; Reactive Oxygen Species; Regulation; Regulator Genes; Research Support; Risk; Risk Factors; Role; Sodium; Sodium Channel; Solid; Structure; Syndrome; Testing; Therapeutic Studies; Transcript; Translating; Variant; Ventricular Remodeling; Woman; Work; cost; fatty acid oxidation; genetic variant; heart function; heart rhythm; high risk; improved; mRNA Expression; mRNA Stability; mRNA Translation; men; mitochondrial metabolism; mortality; mortality risk; novel; novel therapeutics; posttranscriptional; prevent; public health relevance; response; sudden cardiac death; voltage

PROJECT SUMMARY / ABSTRACT Heart failure (HF) and associated arrhythmic sudden cardiac death (SCD) are primary causes of morbidity and mortality worldwide, warranting further investigation of risk factors and pathogenic mechanisms. Precise regulation of cardiac ion channels governing heart rate and rhythm is vital, since slight changes in ion conductance can trigger arrhythmia, elevating one’s risk for SCD. The cardiac action potential is initiated by sodium current through the heart’s primary voltage-gated sodium channel, Nav1.5, encoded by SCN5A. Mutations that alter Nav1.5 function cause arrhythmic syndromes (Brugada, long QT, inherited conduction) and dilated cardiomyopathy (DCM), and common genetic variants within the SCN5A locus have been linked to subtle changes in electrocardiographic measures. However, the impact of altered SCN5A expression on the clinical course of HF and associated non-arrhythmic deaths remains to be thoroughly investigated. Prior studies have shown that SCN5A+/- haploinsufficient mice develop aging-related adverse myocardial remodeling, with increased fibrosis and conduction slowing. We recently discovered that these findings may translate to the clinical setting. Specifically, we identified a common genetic variant that bolsters the activity of a microRNA (miR) binding site within the terminal coding sequence (CDS) of SCN5A. We found that this variant is linked to reduced SCN5A mRNA levels (10-20%) in human hearts, and surprisingly, increased non-arrhythmic death in HF patients. A potential basis for this was identified upon our unexpected finding that SCN5A+/- mouse hearts exhibit increases in oxidative stress and fatty acid oxidation (FAO). These combined preliminary data provide a solid foundation for our central hypothesis that reduced cardiac SCN5A expression elevates one’s susceptibility to subclinical cardiac pathologies that transform into significant risk in the setting of HF. With the core concept being that low Nav1.5 is bad for your heart, our overarching goals are now to 1) define new pathways controlling Nav1.5 levels, 2) delineate how lower Nav1.5 adversely impacts cardiomyocytes, and 3) empirically test if reduced Nav1.5 worsens HF outcomes. In Aim 1, we will characterize novel pathways that regulate SCN5A mRNA stability and translation via its CDS, an expansive region that remains largely underexplored for RNA regulatory functions. In Aim 2, we will define the pathways by which reduced SCN5A expression in cardiomyocytes leads to elevated oxidative stress and FAO. In Aim 3, we will determine if reduced SCN5A expression is sufficient to increase HF-related morbidity and mortality in SCN5A+/- haploinsufficient mice with surgically-induced cardiomyopathy. Overall, this work has strong potential to 1) fill significant knowledge gaps regarding the regulatory control of SCN5A at the RNA level, 2) transform our understanding of Nav1.5 functions beyond well-established roles in cardiac conduction, 3) reinforce the link between reduced SCN5A expression and worse HF, advancing from associative observations to empirical evidence, and 4) prompt future studies aimed at translating these findings towards improved identification and care of high-risk HF patients.

项目摘要 /摘要 心力衰竭（HF）和相关心律不齐的心脏死亡（SCD）是发病率的主要原因 以及全世界的死亡率，警告进一步研究危险因素和致病机制。精确的 控制心率和节奏的心脏离子通道的调节至关重要，因为离子的略有变化 电导会引发心律不齐，从而提高了SCD的风险。心脏动作电位由 钠电流通过心脏的主要电压门控钠通道NAV1.5，由SCN5A编码。 改变NAV1.5功能的突变会导致心律不齐综合征（Brugada，长QT，遗传传导）和 SCN5A基因座内的扩张心肌病（DCM）和常见的遗传变异与微妙 心电图测量的变化。但是，SCN5a表达改变对临床的影响 HF和相关的非心律失常死亡过程仍有待彻底研究。 先前的研究表明，SCN5A +/-单倍弹性的小鼠会发展与老龄化相关的心肌相关的小鼠 重塑，纤维化增加和传导减慢。我们最近发现这些发现可能 转化为临床环境。具体而言，我们确定了一种共同的遗传变异，以增强A的活性 SCN5A的终端编码序列（CD）中的microRNA（miR）结合位点。我们发现这个变体 与人类心脏中的SCN5A mRNA水平降低（10-20％）有关，令人惊讶的是，非心律失常增加 HF患者死亡。在我们意外发现SCN5A +/-鼠标的意外发现的潜在基础 心脏暴露的氧化应激和脂肪酸氧化（FAO）的增加。这些组合的初步数据 为我们的中心假设提供了坚实的基础，该假设降低了心脏SCN5A表达升高 在HF的情况下转变为显着风险的亚临床心脏病理的敏感性。与 核心概念是低NAV1.5对您的心脏不利，我们的总体目标现在为1）定义新的 控制NAV1.5级别的途径，2）描绘NAV1.5如何不利影响心肌细胞，而3） 经验测试是否减少了NAV1.5会使HF结果恶化。在AIM 1中，我们将描述新的途径 通过其CDS调节SCN5A mRNA稳定性和翻译，这是一个额外的区域，在很大程度上保持 无需用于RNA调节函数。在AIM 2中，我们将定义减少SCN5A的途径 心肌细胞中的表达导致氧化应激和粮农组织升高。在AIM 3中，我们将确定是否减少 SCN5A表达足以增加与HF相关的发病率和死亡率，而scn5a +/-单倍弹性小鼠的死亡率 患有手术诱导的心肌病。总体而言，这项工作具有强大的潜力1）填补大量知识 关于RNA级别SCN5A的调节控制的差距，2）改变我们对NAV1.5的理解 功能超出了心脏传导中良好角色的功能，3）加强降低SCN5A之间的联系 表达和较差的HF，从关联观察到经验证据的前进，4）迅速未来 旨在将这些发现转化为改善高风险HF患者的鉴定和护理的研究。