Nicotinamide Riboside Preserves Cardiac Function in a Mouse Model of Dilated Cardiomyopathy.
Nicotinamide Riboside Preserves Cardiac Function in a Mouse Model of Dilated Cardiomyopathy.
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DOI：
10.1161/circulationaha.116.026099
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发表时间：
2018-05-22
期刊：
影响因子：
37.8
通讯作者：
Mericskay M
中科院分区：
文献类型：
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作者：
Diguet N;Trammell SAJ;Tannous C;Deloux R;Piquereau J;Mougenot N;Gouge A;Gressette M;Manoury B;Blanc J;Breton M;Decaux JF;Lavery GG;Baczkó I;Zoll J;Garnier A;Li Z;Brenner C;Mericskay M
心肌代谢损伤是慢性心力衰竭（HF）的一个主要特征。作为燃料氧化和氧化磷酸化的主要辅酶以及能量应激和氧化应激反应信号酶的底物，NAD+ 正在成为包括心力衰竭在内的许多疾病的代谢靶标。对于衰竭心脏中 NAD+ 稳态的调节机制知之甚少。为了探索衰竭心脏中 NAD+ 稳态的可能变化，我们量化了人类衰竭心脏和由心脏 SRF 转录因子耗竭 (SRFHKO) 引发的扩张型心肌病 (DCM) 或由横主动脉缩窄 (TAC) 引发的心脏肥大小鼠模型心脏中 NAD+ 生物合成酶的表达。我们研究了补充 NAD+ 前体对两种小鼠模型心脏功能的影响。我们观察到 DCM 和 TAC 小鼠心脏衰竭的 NAD+ 水平下降了 30%，伴随着回收烟酰胺 (NAM) 前体的 NAMPT 酶表达下降，而磷酸化烟酰胺核苷 (NR) 前体的烟酰胺核苷激酶 NMRK2 增加，DCM 中的水平（40 倍）比 TAC 中的水平（4 倍）更高。与非衰竭对照相比，在人类衰竭心脏活检中也观察到了这种转变。我们发现，Nmrk2 基因是一种 AMPK 和 PPARα 反应性基因，在离体大鼠心肌细胞中会被能量应激和 NAD+ 耗竭所激活。 NR 响应 FK866 介导的 NAMPT 抑制，有效挽救 NAD+ 合成，并刺激心肌细胞中的糖酵解。因此，我们发现食物中补充 NR 可稳定衰竭心脏中的心肌 NAD+ 水平，从而减轻小鼠心力衰竭的发生，在 DCM 中效果更显着，在 TAC 后也能部分减轻。 NR 治疗还可显着提高三种代谢物的心肌水平：烟酸腺嘌呤二核苷酸 (NAAD)、甲基-NAM 和 N1-甲基-4-吡啶酮-5-甲酰胺，这些代谢物可用作治疗的验证生物标志物。数据显示，烟酰胺核苷是 NAD 前体中能量效率最高的，可用于治疗心力衰竭，特别是在扩张型心肌病（一种几乎没有治疗选择的疾病）的情况下。
Myocardial metabolic impairment is a major feature in chronic heart failure (HF). As the major coenzyme in fuel oxidation and oxidative phosphorylation and a substrate for enzymes signaling energy stress and oxidative stress response, NAD+ is emerging as a metabolic target in a number of diseases including HF. Little is known on mechanisms regulating homeostasis of NAD+ in the failing heart. To explore possible alterations of NAD+ homeostasis in the failing heart, we quantified expression of NAD+ biosynthetic enzymes in human failing heart and in the heart of a mouse model of dilated cardiomyopathy (DCM) triggered by SRF transcription factor depletion in the heart (SRFHKO) or of cardiac hypertrophy triggered by transverse aorta constriction (TAC). We studied the impact of NAD+ precursor supplementation on cardiac function in both mouse models. We observed a 30% loss in levels of NAD+ in the murine failing heart of both DCM and TAC mice that was accompanied by a decrease in expression of the NAMPT enzyme that recycles the nicotinamide (NAM) precursor whereas the nicotinamide riboside kinase NMRK2 that phosphorylates the nicotinamide riboside (NR) precursor is increased, to a higher level in the DCM (40 fold) than in TAC (4 fold). This shift was also observed in human failing heart biopsies compared to non-failing controls. We show that the Nmrk2 gene is an AMPK and PPARalpha responsive gene that is activated by energy stress and NAD+ depletion in isolated rat cardiomyocytes. NR efficiently rescues NAD+ synthesis in response to FK866-mediated inhibition of NAMPT and stimulates glycolysis in cardiomyocytes. Accordingly, we show that NR supplementation in food attenuates the development of HF in mice, more robustly in DCM, and partially after TAC, by stabilizing myocardial NAD+ levels in the failing heart. NR treatment also robustly increases the myocardial levels of three metabolites, nicotinic acid adenine dinucleotide (NAAD), methyl-NAM and N1-Methyl-4-pyridone-5-carboxamide, which can be used as validation biomarkers for the treatment. The data show that nicotinamide riboside, the most energy-efficient among NAD precursors, could be useful for treatment of HF notably in the context of DCM, a disease with few therapeutic options.