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Cardioprotection by Nicotinamide Mononucleotide (NMN): Involvement of Glycolysis and Acidic pH

Cardioprotection by Nicotinamide Mononucleotide (NMN): Involvement of Glycolysis and Acidic pH

Sergiy M Nadtochiy, Yves T Wang, Keith Nehrke, Josh Munger, Paul S Brookes

J Mol Cell Cardiol. 2018 Aug;121:155-162.

PMID: 29958828

Abstract:

Stimulation of the cytosolic NAD+ dependent deacetylase SIRT1 is cardioprotective against ischemia-reperfusion (IR) injury. NAD+ precursors including nicotinamide mononucleotide (NMN) are thought to induce cardioprotection via SIRT1. Herein, while NMN protected perfused hearts against IR (functional recovery: NMN 42 ± 7% vs. vehicle 11 ± 3%), this protection was insensitive to the SIRT1 inhibitor splitomicin (recovery 47 ± 8%). Although NMN-induced cardioprotection was absent in Sirt3-/- hearts (recovery 9 ± 5%), this was likely due to enhanced baseline injury in Sirt3-/- (recovery 6 ± 2%), since similar injury levels in WT hearts also blunted the protective efficacy of NMN. Considering alternative cardiac effects of NMN, and the requirement of glycolysis for NAD+, we hypothesized NMN may confer protection in part via direct stimulation of cardiac glycolysis. In primary cardiomyocytes, NMN induced cytosolic and extracellular acidification and elevated lactate. In addition, [U-13C]glucose tracing in intact hearts revealed that NMN stimulated glycolytic flux. Consistent with a role for glycolysis in NMN-induced protection, hearts perfused without glucose (palmitate as fuel source), or hearts perfused with galactose (no ATP from glycolysis) exhibited no benefit from NMN (recovery 11 ± 4% and 15 ± 2% respectively). Acidosis during early reperfusion is known to be cardioprotective (i.e., acid post-conditioning), and we also found that NMN was cardioprotective when delivered acutely at reperfusion (recovery 39 ± 8%). This effect of NMN was not additive with acidosis, suggesting overlapping mechanisms. We conclude that the acute cardioprotective benefits of NMN are mediated in part via glycolytic stimulation, with the downstream protective mechanism involving enhanced ATP synthesis during ischemia and/or enhanced acidosis during reperfusion.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP5690039-A	Splitomicin		5690-03-9	Price

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