Mitochondrial protein hyperacetylation underpins heart failure with preserved ejection fraction in mice
Mitochondrial protein hyperacetylation underpins heart failure with preserved ejection fraction in mice
复制标题
线粒体蛋白过度乙酰化导致小鼠射血分数保留的心力衰竭
DOI：
10.1016/j.yjmcc.2021.12.015
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发表时间：
2022-01-07
影响因子：
5
通讯作者：
Li, Tao
中科院分区：
文献类型：
--
作者：
Liu, Xin;Zhang, Yabing;Li, Tao
超过50%的心力衰竭患者射血分数正常（HFpEF），而不是射血分数降低（HFrEF）。HFpEF的患病率持续增加，而HFpEF的致病机制在很大程度上仍然难以捉摸，仍然缺乏循证治疗。本研究旨在研究HFpEF的代谢特征，并在小鼠模型中测试潜在的治疗干预。通过利用“3-Hit“HFpEF小鼠模型，我们观察到与压力超负荷诱导的HFrEF和成人/老年非心力衰竭（NHF）心脏相比，HFpEF心脏中的整体蛋白质过度乙酰化。乙酰组分析表明，HFpEF心脏特异性的大部分超乙酰化蛋白（74%）位于线粒体中，并富含三羧酸（TCA）循环、氧化磷酸化（OXPHOS）和脂肪酸氧化。进一步的研究表明，HFpEF心脏中升高的蛋白质乙酰化与NAD+/NADH比值降低、线粒体功能受损和TCA循环代谢物耗尽相关。通过补充烟酰胺核苷（NR）30天使NAD+/NADH比率正常化下调乙酰化水平，改善线粒体功能并改善HFpEF表型。因此，我们的研究在HFpEF心脏中鉴定了不同的蛋白质乙酰化模式，并提出NR作为降低乙酰化和减轻小鼠HFpEF表型的有前途的试剂。
Over 50% of patients with heart failure have preserved ejection fraction (HFpEF), rather than reduced ejection fraction (HFrEF). The prevalence of HFpEF continues to increase, while the pathogenic mechanisms underlying HFpEF remain largely elusive and evidence-based therapies are still lacking. This study was designed to investigate the metabolic signature of HFpEF and test the potential therapeutic intervention in a mouse model. By utilizing a "3-Hit " HFpEF mouse model, we observed a global protein hyperacetylation in the HFpEF hearts as compared to the pressure overload-induced HFrEF and adult/aged non-heart failure (NHF) hearts. Acetylome analysis identified that a large proportion of the hyperacetylated proteins (74%) specific to the HFpEF hearts are in mitochondria, and enriched in tricarboxylic acid (TCA) cycle, oxidative phosphorylation (OXPHOS), and fatty acid oxidation. Further study showed that the elevated protein acetylation in the HFpEF hearts was correlated with reduced NAD+/NADH ratio, impaired mitochondrial function, and depleted TCA cycle metabolites. Normalization of NAD+/NADH ratio by supplementation of nicotinamide riboside (NR) for 30 days down regulated the acetylation level, improved mitochondrial function and ameliorated HFpEF phenotypes. Therefore, our study identified a distinct protein acetylation pattern in the HFpEF hearts, and proposed NR as a promising agent in lowering acetylation and mitigating HFpEF phenotypes in mice.