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: 10908777
• 负责人: Kevin D. O'Brien
• 金额: $ 18.18万
• 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 2023-12-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10908777
• 关键词: ADP Ribose Transferases; Address; Anabolism; Animal Model; Animals; Apical; Biochemical Reaction; Bioenergetics; Biological Assay; Blood; Cardiac; Cell Respiration; Cells; Cellular Metabolic Process; Cyclic ADP-Ribose; Data; Day Surgery; Deacetylase; Development; 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; Marketing; 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; 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; 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; pharmacologic; 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源缺乏已与心脏的发展有关 失败（HF）。然而，确切的机制仍然很了解，线粒体靶向疗法是 缺乏。最近，心脏NAD（H）稳态的丧失与线粒体之间的因果关系 HF已提出功能障碍。 NAD（H）氧化还原平衡，即NAD+/NADH比率是关键的调节器 细胞代谢中的多种酶促反应。 NAD+还可以充当sirtuin脱酰基酶的共基质， ADP-核糖转移酶和循环ADP-核糖合成酶，后翻译后修饰蛋白质；包括 酶对能量转导和细胞信号传导很重要。在先前的研究中，我们和其他人观察到 小鼠和人类心脏组织中的NAD+/NADH比和蛋白质乙酰化（LYSAC）的升高 晚期HF的患者。重要的是，通过药理或遗传方法提高NAD+水平 使NAD（H）氧化还原不平衡的丧失和线粒体蛋白高乙酰化的丧失，导致 HF多种动物模型中的心脏功能改善。在初步研究中，我们已经证明 口服NR补充可显着增加全血液NAD+水平并改善外周血 人类中的单核细胞（PMBC）氧化代谢。这些研究为我们提供了独特的 转化研究向前发展的优势，我们知识中的两个主要差距仍然是 解决。一个是，没有研究解决口头NR是否增加NAD+水平的关键问题 在HF患者的心肌中。另一个是，增加NAD+级别受益于HF的机制 不清楚。因此，在这里我们建议确定是否在 手术可以增加NAD+水平并改善在人类失败心肌中获得的线粒体功能 左心室辅助装置（LVAD）植入时间。我们假设参与者随机 到NR将具有更高的心肌NAD+水平，改善线粒体功能并降低 与随机与安慰剂的参与者相比，炎症反应。来自非 - 的初步数据 LVAD植入之前的NR预处理的随机试验研究表明，NR实际上确实增加了 心肌NAD+水平，改善PBMC和心肌的线粒体功能，并减少 PBMC中的炎症反应基因表达。本应用程序中提出的随机研究也将 检查升高细胞内NAD+水平对线粒体和非细胞体的影响 隔室，包括表观遗传修饰和炎症的调节，以及将其关联 心肌的变化，血液的相应变化。通过这项预期的研究确认 NR对人心肌的影响将代表研究NR的潜力的重要进步 首先，在心力衰竭中以线粒体为目标的代谢疗法。

项目成果

Right heart failure after left ventricular assist device: From mechanisms to treatments.

• DOI: 10.3389/fcvm.2022.1023549
• 发表时间: 2022
• 期刊: Frontiers in cardiovascular medicine
• 影响因子: 3.6

Heart after liver transplantation with domino for a highly sensitized patient.

高度敏感患者接受多米诺骨牌肝移植后的心脏。

• DOI: 10.1016/j.healun.2023.06.017
• 发表时间: 2023
• 期刊: The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation
• 作者: Lin,Shin;Minami,Elina;O'Brien,KevinD;Leca,Nicolae;Bhattacharya,Renuka;Biggins,ScottW;Lin,Yiing;Chou-Wu,Elaine;Gimferrer,Idoia;Vanhoy,Steven;Wang,EmilyP;RamasamyBakthavatsalam;Sturdevant,Mark;Dimarakis,Ioannis;Fishbein,Danie
• 通讯作者: Fishbein,Danie

Safety and Tolerability of Nicotinamide Riboside in Heart Failure With Reduced Ejection Fraction.

• DOI: 10.1016/j.jacbts.2022.06.012
• 发表时间: 2022-12
• 期刊: JACC-BASIC TO TRANSLATIONAL SCIENCE
• 影响因子: 9.7
• 作者: Wang, Dennis D.;Airhart, Sophia E.;Zhou, Bo;Shireman, Laura M.;Jiang, Siyi;Rodriguez, Carolina Melendez;Kirkpatrick, James N.;Shen, Danny D.;Tian, Rong;O'Brien, Kevin D.
• 通讯作者: O'Brien, Kevin D.