Mechanistic Studies of NAD+/NADH in Human Heart Failure

NAD/NADH 在人类心力衰竭中的作用机制研究

• 批准号: 10006334
• 负责人: Kevin D. O'Brien
• 金额: $ 77.39万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-01 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10006334
• 关键词: ADP Ribose Transferases; Address; Anabolism; Animal Model; Animals; Biochemical Reaction; Bioenergetics; Biological Assay; Blood; Cardiac; Cell Respiration; Cells; Cellular Metabolic Process; Cyclic ADP-Ribose; Data; Day Surgery; Deacetylase; Dose; Double-Blind Method; Enrollment; Enzymes; Epigenetic Process; Equilibrium; Funding; Gene Expression; Gene Expression Regulation; Heart; Heart failure; Homeostasis; Human; Inflammasome; Inflammation; Inflammatory; Inflammatory Response; Knowledge; Left; Measurement; Measures; Mediating; Metabolic; Mitochondria; Mitochondrial Proteins; Modification; Morphology; Mus; Myocardial; Myocardial dysfunction; Myocardium; NADH; Names; National Heart, Lung, and Blood Institute; Nicotinamide Mononucleotide; Nuclear; Nucleosides; Operating Rooms; Operative Surgical Procedures; Oral; Oxidation-Reduction; Participant; Patients; Peripheral Blood Mononuclear Cell; Pharmacology; Phase; Pilot Projects; Placebos; Protein Acetylation; Proteins; Randomized; Regulation; Respiration; Safety; Sampling; Schedule; Signal Transduction; Sirtuins; Stress; Testing; Time; Tissues; Translating; Translational Research; Treatment Failure; Ventricular; Vitamin B Complex; Whole Blood; body system; cardiogenesis; clinical application; cytokine; dietary supplements; epigenomics; genetic approach; healthy volunteer; heart function; implantation; improved; left ventricular assist device; mitochondrial dysfunction; nicotinamide riboside supplementation; nicotinamide-beta-riboside; peripheral blood; placebo controlled study; preclinical study; pressure; prevent; pyridine; randomized placebo controlled trial; targeted treatment

Project Summary/Abstract Mitochondrial dysfunction and energy deficiency have been strongly implicated in the development of heart failure (HF). Yet, the exact mechanisms remain poorly understood and mitochondria-targeted therapy is lacking. Recently, a causal relationship between the loss of cardiac NAD(H) homeostasis and mitochondrial dysfunction has been proposed in HF. The NAD(H) redox balance, i.e. NAD+/NADH ratio, is a critical regulator of multiple enzymatic reactions in cell metabolism. NAD+ also functions as a co-substrate for sirtuin deacylase, ADP-ribose transferases, and cyclic ADP-ribose synthases that post-translationally modify proteins; including enzymes important for energy transduction and cell signaling. In prior studies, we and others have observed lower NAD+/NADH ratio and elevated protein acetylation (LysAc) in cardiac tissue from mice and human patients of advanced HF. Importantly, increasing NAD+ levels by pharmacological or genetic approach normalized the loss of NAD(H) redox imbalance and reversed mitochondrial protein hyperacetylation leading to improved cardiac function in multiple animal models of HF. In the preliminary studies, we have demonstrated that oral NR supplementation significantly increases whole blood NAD+ levels and improves peripheral blood mononuclear cell (PMBC) oxidative metabolism in humans. While these studies provide us the unique advantage of moving the translational research forward, two major gaps in our knowledge remain to be addressed. One is that no study has addressed the critical questions of whether oral NR increases NAD+ levels in the myocardium of HF patients. The other is that the mechanisms by which increasing NAD+ level benefit HF is unclear. Therefore, here we propose to determine whether oral NR supplementation for eight days prior to surgery can increase NAD+ levels and improve mitochondrial function in human failing myocardium obtained at the time of left ventricular assist device (LVAD) implantation. We hypothesize that participants randomized to NR will have higher myocardial NAD+ levels, improved mitochondrial function and reduced inflammatory response as compared to participants randomized to placebo. Preliminary data from a non- randomized Pilot Study of NR pretreatment prior to LVAD implantation suggest that NR does, in fact, increase myocardial NAD+ levels, improve mitochondrial function in PBMCs and myocardium, and decreases inflammatory response gene expression in PBMCs. The randomized study proposed in this application also will examine the effects of increasing intracellular NAD+ level on mitochondrial and non-mitochondrial compartments, including epigenetic modifications and regulation of inflammation, as well as correlate these changes in myocardium with corresponding changes in blood. Confirmation by this study of the anticipated effects of NR on human myocardium would represent an important advance in investigating the potential of NR as the first, mitochondria-targeted metabolic therapy in heart failure.

项目摘要/摘要 线粒体功能障碍和能量缺乏与心脏的发育密切相关。 故障(HF)。然而，确切的机制仍不清楚，线粒体靶向治疗是 缺乏。最近，心肌NAD(H)动态平衡的丧失与线粒体之间的因果关系 功能障碍已被提出在心力衰竭。NAD(H)氧化还原平衡，即NAD+/NADH比率，是一个关键的调节因素 细胞新陈代谢中的多种酶反应。NAD+还作为sirtuin脱酰基酶的共底物， 翻译后修饰蛋白质的ADP-核糖转移酶和环状ADP-核糖合成酶； 对能量转导和细胞信号转导很重要的酶。在之前的研究中，我们和其他人观察到 小鼠和人心肌组织中NAD+/NADH比值降低和蛋白乙酰化(LysAc)升高 晚期心力衰竭患者。重要的是，通过药理学或遗传学方法提高NAD+水平 使NAD(H)氧化还原失衡的丧失正常化，并逆转线粒体蛋白超乙酰化导致 改善多种心力衰竭动物模型的心功能。在初步研究中，我们已经证明 口服NR可显著提高全血NAD+水平，改善外周血 人体内的单核细胞氧化代谢。虽然这些研究为我们提供了独特的 推动翻译研究向前发展的优势，我们知识中的两个主要差距仍然是 地址。其中之一是，没有研究解决口服NR是否会增加NAD+水平的关键问题 在心力衰竭患者的心肌中。另一种是提高NAD+水平有利于心衰的机制 目前还不清楚。因此，我们建议在此确定口服NR补充剂前8天是否 手术可提高衰竭心肌NAD+水平并改善线粒体功能 左心室辅助装置(LVAD)植入时间。我们假设参与者随机选择 TO-NR将使心肌NAD+水平升高，线粒体功能改善，减少 炎症反应与随机服用安慰剂的参与者相比。非政府组织的初步数据 在植入左冠状动脉前置入术前对NR进行的随机先导研究表明，事实上，NR确实增加了 心肌NAD+水平，改善PBMC和心肌线粒体功能，并降低 外周血单核细胞炎症反应基因的表达。本申请中提出的随机研究也将 检测细胞内NAD+水平升高对线粒体和非线粒体的影响 隔室，包括表观遗传修饰和炎症的调节，以及它们之间的关联 心肌的变化与血液的相应变化。通过这项研究证实了预期的 NR对人心肌的影响将是研究NR潜能的一个重要进展 作为首个针对心力衰竭的线粒体靶向代谢疗法。