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J Mol Cell Cardiol. 2017 Nov;112:64-73. doi: 10.1016/j.yjmcc.2017.09.001. Epub 2017 Sep 5.

Short-term administration of Nicotinamide Mononucleotide preserves cardiac mitochondrial homeostasis and prevents heart failure.

Author information

1
Case Cardiovascular Research Institute, Case Western Reserve University School of Medicine, University Hospitals Cleveland Medical Center, Cleveland, OH 44106, USA.
2
Department of Cardiology, Tongji Hospital, Tongji University, Shanghai 20065, China.
3
Case Cardiovascular Research Institute, Case Western Reserve University School of Medicine, University Hospitals Cleveland Medical Center, Cleveland, OH 44106, USA; Department of Physiology and Biophysics, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA.
4
Electron Microscopy Core Facility, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA.
5
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
6
Case Cardiovascular Research Institute, Case Western Reserve University School of Medicine, University Hospitals Cleveland Medical Center, Cleveland, OH 44106, USA. Electronic address: xudong.liao@case.edu.

Abstract

Heart failure is associated with mitochondrial dysfunction so that restoring or improving mitochondrial health is of therapeutic importance. Recently, reduction in NAD+ levels and NAD+-mediated deacetylase activity has been recognized as negative regulators of mitochondrial function. Using a cardiac specific KLF4 deficient mouse line that is sensitive to stress, we found mitochondrial protein hyperacetylation coupled with reduced Sirt3 and NAD+ levels in the heart before stress, suggesting that the KLF4-deficient heart is predisposed to NAD+-associated defects. Further, we demonstrated that short-term administration of Nicotinamide Mononucleotide (NMN) successfully protected the mutant mice from pressure overload-induced heart failure. Mechanically, we showed that NMN preserved mitochondrial ultrastructure, reduced ROS and prevented cell death in the heart. In cultured cardiomyocytes, NMN treatment significantly increased long-chain fatty acid oxidation despite no direct effect on pyruvate oxidation. Collectively, these results provide cogent evidence that hyperacetylation of mitochondrial proteins is critical in the pathogenesis of cardiac disease and that administration of NMN may serve as a promising therapy.

KEYWORDS:

Heart failure; Mitochondria; NAD; Pressure overload; Protein hyperacetylation

PMID:
28882480
DOI:
10.1016/j.yjmcc.2017.09.001
[Indexed for MEDLINE]

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