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Cardioprotection by nicotinamide mononucleotide (NMN): Involvement of glycolysis and acidic pH.

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.

SUBMITTER: Nadtochiy SM

PROVIDER: S-EPMC6103815 | biostudies-literature | 2018 Aug

REPOSITORIES: biostudies-literature

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Cardioprotection by nicotinamide mononucleotide (NMN): Involvement of glycolysis and acidic pH.

Nadtochiy Sergiy M SM Wang Yves T YT Nehrke Keith K Munger Josh J Brookes Paul S PS

Journal of molecular and cellular cardiology 20180626

Stimulation of the cytosolic NAD<sup>+</sup> dependent deacetylase SIRT1 is cardioprotective against ischemia-reperfusion (IR) injury. NAD<sup>+</sup> 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 abse ...[more]

PMID: 29958828

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Project description:ObjectiveUltraviolet light is an important environmental factor that induces skin oxidation, inflammation, and other diseases. Nicotinamide mononucleotide (NMN) has the effect of anti-oxidation and improving various physiological processes. This study explores the protective effect of NMN monomers given via intraperitoneal injection on UVB-induced photodamage.MethodsWe used a murine model of UVB-induced photodamage to evaluate the effect of an NMN monomer on photoaging skin by assessing skin and liver tissue sections, serum and skin oxidative stress levels, inflammatory markers, mRNA expression, and protein expression of skin- and liver-related genes.ResultsThe results showed that NMN treatment blocked UVB-induced photodamage in mice, maintaining normal structure and amount of collagen fibers, normal thickness of epidermis and dermis, reducing the production of mast cells, and maintaining complete organized skin structure. NMN intraperitoneal injection also maintained the normal morphology of the mouse liver after UVB exposure. Meanwhile, NMN intraperitoneal injection was found to increase antioxidant ability and regulate the proinflammatory response of the skin and liver to UVB irradiation by enhancing the activity of antioxidant enzymes, release of anti-inflammatory cytokines, reduction of hydrogen peroxide production (H2O2), and decreased inflammatory cytokines. Furthermore, RT-qPCR results indicated that NMN reduced oxidative stress of skin and liver by promoting the activation of the AMP-activated protein kinase (AMPK) signaling pathway and further increasing the expression of downstream antioxidant genes of AMPK. RT-qPCR results also revealed that NMN treatment could downregulate the mRNA expression of interleukin (IL)-6, interleukin (IL)-1β, and tumor necrosis factor (TNF)-α, and upregulate NF-kappa-B inhibitor-α (IκB-α) and interleukin (IL)-10 by inhibiting the activation of nuclear factor-κBp65 (NFκB-p65). Finally, NMN upregulated AMPK, IκB-α, SOD1, and CAT in the skin and downregulated NF-κBp65 protein expression, which is in line with the RT-qPCR results.ConclusionBased on the above results, NMN monomer treatment with intraperitoneal injection also block the photodamage caused by UVB irradiation in mice by regulating the oxidative stress response and inflammatory response.

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Cardioprotection by nicotinamide mononucleotide (NMN): Involvement of glycolysis and acidic pH.

Publications

Cardioprotection by nicotinamide mononucleotide (NMN): Involvement of glycolysis and acidic pH.

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