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

项目摘要 在美国，心脏病每年导致超过65万人死亡，近一半的成年人死于心脏病。 目前患有某种心血管疾病目前还没有治愈性的治疗方法 除了心脏移植因此，非常需要更好的治疗干预。 心力衰竭可能需要数年时间才能发展，但最终的特征是心输出量减少。 有相当多的研究表明， 心肌细胞在这个阶段，这有助于心脏功能障碍和左心室的不良重塑 脑室本申请中详述的假设提出烟酰胺腺嘌呤 线粒体中的二核苷酸（NAD+）缺乏足以引起心力衰竭。最近 文献表明缺血性损伤期间组织水平的NAD+下降。NAD+前体已经被 在多个临床前模型中发现对心力衰竭有治疗作用。生成的初步数据 我们的实验室表明NAD+前体烟酰胺核苷（NR）预防心脏功能障碍， 保护线粒体功能，并改善弗里德赖希共济失调（FA）模型的存活率，其中 小鼠通常发展为进行性肥厚型心肌病。这一结果表明，NAD+ 虚损可能参与了FA心力衰竭的发病机制。或者，它提供了临床前 有证据表明，即使没有NAD+缺乏，NR也能治疗FA，这表明增加NAD+ 在线粒体应激下，心脏组织中的水平可以保护心脏功能。解决 鉴于以上几点，本提案首先旨在确定是否观察到低线粒体NAD+水平 以及用NR离体增加线粒体NAD+合成是否可以直接 支持线粒体呼吸（目的1）。该提案还旨在定义代谢 心肌细胞线粒体NAD+缺乏的后果，以确定是否 线粒体NAD+丢失显示了体内肥大心脏的特征性代谢（目的 2）。总之，这组实验将证明NAD+下降是否是代谢性的。 结果共济失调蛋白损失和线粒体损伤，并确定线粒体的重要性， NAD+维持在支持心肌细胞的正常代谢中。此外，它将提供 对NAD+前体保护线粒体- 功能障碍介导的心力衰竭，这将为未来进行性心力衰竭的治疗干预提供信息。 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.