Mitochondrial protein hyperacetylation underpins heart failure with preserved ejection fraction in mice

J Mol Cell Cardiol. 2022 Apr:165:76-85. doi: 10.1016/j.yjmcc.2021.12.015. Epub 2022 Jan 5.

Abstract

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.

Keywords: Heart failure; Mitochondria; NAD(+); Nicotinamide riboside; Protein acetylation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Animals
  • Disease Models, Animal
  • Heart Failure*
  • Humans
  • Mice
  • Mitochondrial Proteins
  • NAD
  • Stroke Volume
  • Ventricular Function, Left

Substances

  • Mitochondrial Proteins
  • NAD