NAD(+) Repletion Reverses Heart Failure With Preserved Ejection Fraction.
NAD(+) Repletion Reverses Heart Failure With Preserved Ejection Fraction.
复制标题
DOI：
10.1161/circresaha.120.317046
复制
发表时间：
2021-05-28
影响因子：
20.1
通讯作者：
Hill JA
中科院分区：
文献类型：
--
作者：
Tong D;Schiattarella GG;Jiang N;Altamirano F;Szweda PA;Elnwasany A;Lee DI;Yoo H;Kass DA;Szweda LI;Lavandero S;Verdin E;Gillette TG;Hill JA
射血分数保留性心力衰竭（HFpEF）是一种致死性临床综合征，目前尚无有效的治疗方法。我们最近在小鼠中证明，代谢和高血压应激的组合概括了人类HFpEF的关键特征。使用这种新的临床前HFpEF模型，我们开始定义和操纵HFpEF心肌中发生的代谢失调。我们观察到线粒体脂肪酸氧化损伤与途径中关键酶的超乙酰化有关。沉默调节蛋白3的下调和继发于受损的NAD+补救途径的NAD+缺乏促成了这种线粒体蛋白的过度乙酰化。在HFpEF患者的心脏组织中证实了参与NAD+生物合成的基因表达受损。用烟酰胺核苷或NAD+生物合成的直接激活剂补充HFpEF小鼠导致线粒体功能的改善和HFpEF表型的改善。总的来说，这些研究表明HFpEF与心肌线粒体功能障碍相关，并揭示了NAD+补充作为该综合征的一种有前途的治疗方法。
Heart failure with preserved ejection fraction (HFpEF) is a mortal clinical syndrome without effective therapies. We recently demonstrated in mice that a combination of metabolic and hypertensive stress recapitulates key features of human HFpEF. Using this novel preclinical HFpEF model, we set out to define and manipulate metabolic dysregulations occurring in HFpEF myocardium. We observed impairment in mitochondrial fatty acid oxidation associated with hyperacetylation of key enzymes in the pathway. Down-regulation of sirtuin 3 and deficiency of NAD+ secondary to an impaired NAD+ salvage pathway contribute to this mitochondrial protein hyperacetylation. Impaired expression of genes involved in NAD+ biosynthesis was confirmed in cardiac tissue from HFpEF patients. Supplementing HFpEF mice with nicotinamide riboside or a direct activator of NAD+ biosynthesis led to improvement in mitochondrial function and amelioration of the HFpEF phenotype. Collectively, these studies demonstrate that HFpEF is associated with myocardial mitochondrial dysfunction and unveil NAD+ repletion as a promising therapeutic approach in the syndrome.