射血分数保留的心力衰竭
乙酰化
NAD+激酶
心力衰竭
内科学
线粒体
射血分数
氧化磷酸化
柠檬酸循环
医学
心脏病学
内分泌学
生物化学
化学
新陈代谢
基因
酶
作者
Xin Liu,Yabing Zhang,Yan Deng,Lin Yang,Wei Ou,Maodi Xie,Lin Ding,Chunling Jiang,Hai Yu,Qian Li,Tao Li
标识
DOI:10.1016/j.yjmcc.2021.12.015
摘要
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 downregulated 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.
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