Loss of mitochondrial NAD+ as a unifying cause of heart failure

项目摘要 美国每年有超过65万人死于心脏病，将近一半的成年人死于心脏病 目前患有某种形式的心血管疾病。目前还没有根治方法。 除了心脏移植以外的其他选择。因此，非常需要更好的治疗干预措施。 心力衰竭可能需要数年时间才能发展，但最终特征是心输出量减少。 有相当多的研究表明，不适应的代谢重新编程 心肌细胞在这个阶段，这是导致心脏功能障碍和左心室不良重构的原因 脑室。本申请中详述的假说提出烟酰胺腺嘌呤 线粒体中的二核苷酸(NAD+)缺乏足以导致心力衰竭。近期 文献表明，组织水平的NAD+在缺血损伤期间下降。NAD+的前身是 在多种临床前模型中被发现对心力衰竭有治疗作用。初步数据生成于 我们的实验室表明，NAD+前体烟酰胺核苷(NR)可以预防心脏功能障碍， 保护线粒体功能，改善Friedreich共济失调(FA)模型的存活率 小鼠通常会发展成进行性肥厚型心肌病。这一结果表明，NAD+ 虚证可能参与了FA心力衰竭的发病机制。或者，它提供临床前 有证据表明，即使在没有NAD+缺乏的情况下，NR对FA也是有治疗作用的，这表明促进NAD+ 在线粒体应激下，心脏组织中的水平可以保护心脏功能。致信地址 这些点，这个建议首先旨在确定是否观察到低线粒体NAD+水平 随着Frataxin的丢失，NR体外是否能直接增加线粒体NAD+的合成 支持线粒体呼吸(目标1)。这项提案还旨在定义新陈代谢 线粒体NAD+缺乏对心肌细胞的影响，以确定 线粒体NAD+丢失显示肥厚心脏体内代谢的特征(目的 2)。总之，这组实验将证明NAD+下降是否是一种新陈代谢 Frataxin丢失和线粒体损伤的后果，并确定线粒体的重要性 NAD+维持支持心肌细胞的正常代谢。此外，它将提供 从机制上理解NAD+前体保护线粒体的具体作用 功能障碍介导的心力衰竭，这将为未来进展性治疗干预提供信息 心脏病。

Project Summary Heart disease results in over 650,000 deaths per year in the United States, and nearly half of all adults are currently living with some form of cardiovascular disease. Currently there is no curative treatment option except for a heart transplant. Thus, there is significant need for better therapeutic interventions. Heart failure can take years to develop, but is ultimately characterized by a reduction in cardiac output. There is a considerable body of research demonstrating maladaptive metabolic reprogramming of cardiomyocytes at this stage, which contributes to heart dysfunction and adverse remodeling of the left ventricle. The hypothesis detailed in this application proposes that nicotinamide adenine dinucleotide (NAD+) deficiency in the mitochondria is sufficient to cause heart failure. Recent literature demonstrates tissue-level NAD+ decline during ischemic injury. NAD+ precursors have been found to be therapeutic for heart failure in multiple pre-clinical models. Preliminary data generated in our lab suggests that the NAD+ precursor nicotinamide riboside (NR) prevented heart dysfunction, protected mitochondrial function, and improved survival in a model of Friedreich’s Ataxia (FA), in which mice typically develop progressive hypertrophic cardiomyopathy. This result suggests that NAD+ deficiency may be involved in the pathogenesis of heart failure in FA. Alternatively, it provides preclinical evidence that NR is therapeutic in FA even without NAD+ deficiency, suggesting that boosting NAD+ levels in the heart tissue can be protective of heart function under mitochondrial stress. To address these points, this proposal first aims to determine whether low mitochondrial NAD+ levels are observed with loss of frataxin, and whether increasing mitochondrial NAD+ synthesis with NR ex vivo can directly support mitochondrial respiration (Aim 1). This proposal also aims to define the metabolic consequences of mitochondrial NAD+ deficiency in cardiomyocytes, to determine whether mitochondrial NAD+ loss demonstrates characteristic metabolism of the hypertrophic heart in vivo (Aim 2). Together, this set of experiments will demonstrate whether NAD+ decline is a metabolic consequence of frataxin loss and mitochondrial damage, and define the importance of mitochondrial NAD+ maintenance in supporting the normal metabolism of cardiomyocytes. Further, it will provide mechanistic understanding of the specific action of NAD+ precursors to protect against mitochondrial- dysfunction mediated heart failure, which will inform future therapeutic interventions in progressive heart disease.