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: 10327278
• 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 2023-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10327278
• 关键词: Action Potentials; Address; Aging; Anabolism; Arrhythmia; Binding Sites; Bioinformatics; Biology; Cardiac; Cardiac Myocytes; Cardiac health; Cardiomyopathies; Caring; Cessation of life; Clinical; Code; Data; Dilated Cardiomyopathy; Disease; Electrophysiology (science); Exhibits; Fibrosis; Foundations; Future; Gene Expression; Genetic Transcription; Genetic Translation; Goals; Grant; Healthcare Systems; Heart; Heart Diseases; Heart Rate; Heart failure; Human; Inherited; Investigation; Ion Channel; Ions; Knock-out; 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; 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; men; mitochondrial metabolism; mortality; mortality risk; novel; novel therapeutics; 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)和相关的心律失常性心脏性猝死(SCD)是发病率的主要原因 世界范围内的风险和死亡率，需要进一步研究风险因素和致病机制。精确 调节心率和节律的心脏离子通道是至关重要的，因为离子的轻微变化 电导可引发心律失常，增加患SCD的风险。心脏动作电位是由 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失常综合征(Brugada、长QT、遗传性传导)和 扩张型心肌病(DCM)和SCN5A基因座内常见的遗传变异与微妙 心电指标的变化。然而，SCN5A表达改变对临床的影响 心衰及相关非心律失常死亡的病程仍有待彻底调查。 先前的研究表明，SCN5A+/-单倍体缺陷小鼠会发生与衰老相关的不良心肌梗死 重塑，纤维化加重，传导减慢。我们最近发现，这些发现可能 翻译成临床环境。具体地说，我们确定了一种常见的基因变异，它支持一种 SCN5A末端编码序列(CDS)内的microRNA(MiR)结合位点。我们发现这个变种 与人类心脏中SCN5A mRNA水平降低(10%-20%)有关，令人惊讶的是，非心律失常增加 心力衰竭患者死亡。这一发现的潜在基础是我们意外发现SCN5A+/-小鼠 心脏表现出氧化应激和脂肪酸氧化增加(粮农组织)。这些综合的初步数据 为我们的中心假设提供了坚实的基础，即心脏SCN5A表达减少会提高一个人的 对亚临床心脏病理的易感性，这些疾病在心力衰竭的背景下转化为重大风险。与 核心概念是低NaV1.5对心脏有害，我们现在的首要目标是1)定义新的 控制NaV1.5水平的途径，2)描述较低的NaV1.5如何对心肌细胞产生不利影响，以及3) 经验性测试NaV1.5降低是否会恶化心力衰竭的结局。在目标1中，我们将描述新的路径 通过其CDS调控SCN5A mRNA的稳定性和翻译，CDS是一个在很大程度上仍然存在的扩张区 对RNA调节功能的研究不足。在目标2中，我们将定义降低SCN5A的途径 在心肌细胞中的表达导致氧化应激和粮农组织的升高。在目标3中，我们将确定是否减少 SCN5A表达足以增加SCN5A+/-单倍体缺陷小鼠心衰相关的发病率和死亡率 患有外科手术引起的心肌病。总体而言，这项工作有很强的潜力来填补重要的知识 在RNA水平上对SCN5A的调控存在差距，2)改变了我们对NaV1.5的理解 心脏传导中已确立的作用之外的功能，3)加强了SCN5A减少之间的联系 表达和更糟糕的HF，从联想观察到经验证据，以及4)提示未来 旨在将这些发现转化为改善高危心力衰竭患者的识别和护理的研究。