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Evaluating NAD Supplementation as a Novel Treatment for Arrhythmias

评估 NAD 补充剂作为心律失常的新型治疗方法

基本信息

批准号：
10381462
负责人：
Charles M Brenner
金额：
$ 58.26万
依托单位：
UNIVERSITY OF IOWA
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-04-01 至 2024-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10381462
关键词：
Acetylation Action Potentials Affect Arrhythmia Binding Binding Proteins Bioenergetics Brugada syndrome Cardiac Cardiac Myocytes Cell Line Cell membrane Cells Characteristics DNA Damage Data Deacetylation Dihydroxyacetone Phosphate Dilated Cardiomyopathy Disease Dose Electrocardiogram Electrophysiology (science)Engineering Enzymes Gel Genes Genetic Transcription Glycerol-3-Phosphate Dehydrogenase Goals Heart Heart Atrium Heart failure In Vitro Inherited Ion Channel Laboratories Mediating Membrane Metabolic Metabolism Mus Muscle Cells Mutation Myocardial NADH Neonatal Niacinamide Oxidation-Reduction Oxidative Phosphorylation Oxidoreductase Pharmacology Phosphorylation Play Poly(ADP-ribose) Polymerases Post-Translational Protein Processing Predisposition Property RNA Splicing Rattus Reactive Oxygen Species Reporting Role SIRT1 gene Signal Transduction Sirtuins Sodium Sodium Channel Structure Sudden Death Sudden infant death syndrome Supplementation Syndrome System Testing Translations age related alpha Actinin alpha-glycerophosphoric acid dietary in vivo inhibitor inorganic phosphate loss of function mutation metabolome mouse model nicotinamide riboside supplementation nicotinamide-beta-riboside novel prevent response trafficking treatment effect

项目摘要

The inward depolarizing Na+ current (INa) through the cardiac Na+ channel Nav1.5, encoded by SCN5A, plays a critical role in regulating the action potential of myocytes in the heart. Nav1.5 post- translational modifications (PTMs) and binding proteins can alter channel abundance and/or electrophysiological properties. Loss of function mutations in SCN5A cause inherited arrhythmia syndromes including Brugada syndrome (BrS) and conduction system disease by changes in transcription, translation, channel properties and membrane trafficking. Alterations in Nav1.5 can also exacerbate arrhythmias in common acquired conditions such as heart failure. NAD+ and NADH are critical regulators of myocardial bioenergetics and redox state, and NAD+ is a required substrate for sirtuins that regulate acetylation. Our laboratory reported that mutations in the NAD+/NADH dependent enzyme Gylcerol-3 Phosphate Dehydrogenase-1 Like (GPD1-L) cause BrS by altering Nav1.5 membrane trafficking. We and others then showed that NAD+ increases INa in cell lines and cardiac myocytes, at least in part through changes in reactive oxygen species (ROS) and PKC- mediated phosphorylation in the intracellular Nav1.5 Domain III-IV linker. We have engineered Gpd1l- targeted mice that have decreased INa, conduction disease, arrhythmias and altered Nav1.5 PTMs. Nicotinamide Riboside (NR), a highly bioavailable NAD+ precursor, increases INa in heterologous expression systems and myocytes, and shortens QRS duration in mice. The mechanism(s) by which NAD+ supplementation alters Nav1.5 membrane trafficking and INa remains unclear. In addition, how multiple PTMs alter Nav1.5 and INa in a coordinated manner has not been studied. The central hypothesis of this proposal is that cellular metabolism alters the NAD+ metabolome, regulating Nav1.5 by coordinated interactions of PTMs and binding proteins that act at the Nav1.5 Domain III-IV linker. To test this hypothesis, we will 1) Determine how NAD+ precursors and inhibitors modify the NAD+ metabolome, redox state, Nav1.5 PTMs, INa and arrhythmias using cardiac myocytes and mouse models; 2) Determine whether NAD+ precursors act in a coordinated manner at the Nav1.5 Domain III-IV linker via SIRT1-mediated deacetylation, PKC-mediated phosphorylation and α-actinin 2 binding; and 3) Identify the Nav1.5 PTMs modulated by GPD1-L. The primary goal of this proposal is to identify the mechanisms by which NAD+ metabolism affects Nav1.5 expression and function. Ultimately, we hope to determine whether increasing membrane Nav1.5 with NAD+ precursors or other metabolic modulators can prevent arrhythmias in inherited Na+ channel deficiency syndromes and in more common conditions such as heart failure.

向内去极化Na+电流（INa）通过心脏Na+通道Nav1.5，由