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Nicotinamide mononucleotide, an intermediate of NAD+ synthesis, protects the heart from ischemia and reperfusion.

Yamamoto T, Byun J, Zhai P, Ikeda Y, Oka S, Sadoshima J - PLoS ONE (2014)

Bottom Line: The protective effect of NMN was accompanied by decreases in acetylation of FoxO1, but it was not obvious in Sirt1 KO mice, suggesting that the effect of NMN is mediated through activation of Sirt1.The protective effect of CR against I/R injury was not significant in cardiac-specific Sirt1 KO mice, suggesting that the protective effect of CR is in part mediated through the Nampt-Sirt1 pathway.In conclusion, exogenous application of NMN and CR protects the heart by both mimicking IPC and activating Sirt1.

View Article: PubMed Central - PubMed

Affiliation: Department of Cell Biology and Molecular Medicine, Cardiovascular Research Institute, Rutgers New Jersey Medical School, Newark, New Jersey, United States of America.

ABSTRACT
Nicotinamide phosphoribosyltransferase (Nampt), the rate-limiting enzyme for nicotinamide adenine dinucleotide (NAD+) synthesis, and Sirt1, an NAD+-dependent histone deacetylase, protect the heart against ischemia/reperfusion (I/R). It remains unknown whether Nampt mediates the protective effect of ischemic preconditioning (IPC), whether nicotinamide mononucleotide (NMN, 500 mg/kg), a product of Nampt in the NAD+ salvage pathway, mimics the effect of IPC, or whether caloric restriction (CR) upregulates Nampt and protects the heart through a Sirt1-dependent mechanism. IPC upregulated Nampt protein, and the protective effect of IPC against ischemia (30 minutes) and reperfusion (24 hours) was attenuated at both early and late phases in Nampt +/- mice, suggesting that Nampt plays an essential role in mediating the protective effect of IPC. In order to mimic the effect of Nampt, NMN was administered by intraperitoneal injection. NMN significantly increased the level of NAD+ in the heart at baseline and prevented a decrease in NAD+ during ischemia. NMN protected the heart from I/R injury when it was applied once 30 minutes before ischemia or 4 times just before and during reperfusion, suggesting that exogenous NMN protects the heart from I/R injury in both ischemic and reperfusion phases. The protective effect of NMN was accompanied by decreases in acetylation of FoxO1, but it was not obvious in Sirt1 KO mice, suggesting that the effect of NMN is mediated through activation of Sirt1. Compared to control diet (90% calories), CR (60% calories for 6 weeks) in mice led to a significant reduction in I/R injury, accompanied by upregulation of Nampt. The protective effect of CR against I/R injury was not significant in cardiac-specific Sirt1 KO mice, suggesting that the protective effect of CR is in part mediated through the Nampt-Sirt1 pathway. In conclusion, exogenous application of NMN and CR protects the heart by both mimicking IPC and activating Sirt1.

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NAD+ content after NMN administration.A-C, NMN (500 mg/kg) or vehicle (phosphate buffered saline) was administered to mice and the hearts were harvested at the indicated time points. n = 3 to 4. A, NAD+ contents. B, NADH contents. C, NAD+/NADH ratio. D, The protocol for NMN injection followed by 30 minutes ischemia for the measurement of NAD+, NADH and NAD+/NADH in E-G. E, NAD+ contents. F, NADH contents. G, NAD+/NADH ratio. In E-G, n = 4. In A-C and E-G, n.s., not significant, * p<0.05, ** p<0.01.
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pone-0098972-g003: NAD+ content after NMN administration.A-C, NMN (500 mg/kg) or vehicle (phosphate buffered saline) was administered to mice and the hearts were harvested at the indicated time points. n = 3 to 4. A, NAD+ contents. B, NADH contents. C, NAD+/NADH ratio. D, The protocol for NMN injection followed by 30 minutes ischemia for the measurement of NAD+, NADH and NAD+/NADH in E-G. E, NAD+ contents. F, NADH contents. G, NAD+/NADH ratio. In E-G, n = 4. In A-C and E-G, n.s., not significant, * p<0.05, ** p<0.01.

Mentions: Since Nampt is the rate-limiting enzyme for NAD+ synthesis [11], NAD+ content in the heart may be increased by the administration of NMN, the product of the enzymatic reaction of Nampt with its substrate, nicotinamide. We measured NAD+ and NADH contents 30 min, 1 hour and 3 hours after intraperitoneal (i.p.) injection (500 mg/kg body weight) of NMN (Figure 3A and 3B). Both NAD+ and NADH contents were increased as early as 30 min after the administration of NMN. The NAD+/NADH ratio was not significantly affected by NMN (Figure 3C). Since NMN increases the NAD+ content 30 min after injection and the increase persists for more than 1 hour, we tested the effect of NMN upon the ischemia-induced reduction in the NAD+ content by injecting it 30 min before ischemia and harvesting the heart after 30 min of ischemia (Figure 3D). As expected, NMN increased both NAD+ content and the NAD+/NADH ratio in the heart with or without ischemia. Moreover, the decreases in the NAD+ content and NAD+/NADH ratio observed after 30 min of ischemia in PBS-injected mice were normalized after NMN administration (Figure 3E-G).


Nicotinamide mononucleotide, an intermediate of NAD+ synthesis, protects the heart from ischemia and reperfusion.

Yamamoto T, Byun J, Zhai P, Ikeda Y, Oka S, Sadoshima J - PLoS ONE (2014)

NAD+ content after NMN administration.A-C, NMN (500 mg/kg) or vehicle (phosphate buffered saline) was administered to mice and the hearts were harvested at the indicated time points. n = 3 to 4. A, NAD+ contents. B, NADH contents. C, NAD+/NADH ratio. D, The protocol for NMN injection followed by 30 minutes ischemia for the measurement of NAD+, NADH and NAD+/NADH in E-G. E, NAD+ contents. F, NADH contents. G, NAD+/NADH ratio. In E-G, n = 4. In A-C and E-G, n.s., not significant, * p<0.05, ** p<0.01.
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Show All Figures
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pone-0098972-g003: NAD+ content after NMN administration.A-C, NMN (500 mg/kg) or vehicle (phosphate buffered saline) was administered to mice and the hearts were harvested at the indicated time points. n = 3 to 4. A, NAD+ contents. B, NADH contents. C, NAD+/NADH ratio. D, The protocol for NMN injection followed by 30 minutes ischemia for the measurement of NAD+, NADH and NAD+/NADH in E-G. E, NAD+ contents. F, NADH contents. G, NAD+/NADH ratio. In E-G, n = 4. In A-C and E-G, n.s., not significant, * p<0.05, ** p<0.01.
Mentions: Since Nampt is the rate-limiting enzyme for NAD+ synthesis [11], NAD+ content in the heart may be increased by the administration of NMN, the product of the enzymatic reaction of Nampt with its substrate, nicotinamide. We measured NAD+ and NADH contents 30 min, 1 hour and 3 hours after intraperitoneal (i.p.) injection (500 mg/kg body weight) of NMN (Figure 3A and 3B). Both NAD+ and NADH contents were increased as early as 30 min after the administration of NMN. The NAD+/NADH ratio was not significantly affected by NMN (Figure 3C). Since NMN increases the NAD+ content 30 min after injection and the increase persists for more than 1 hour, we tested the effect of NMN upon the ischemia-induced reduction in the NAD+ content by injecting it 30 min before ischemia and harvesting the heart after 30 min of ischemia (Figure 3D). As expected, NMN increased both NAD+ content and the NAD+/NADH ratio in the heart with or without ischemia. Moreover, the decreases in the NAD+ content and NAD+/NADH ratio observed after 30 min of ischemia in PBS-injected mice were normalized after NMN administration (Figure 3E-G).

Bottom Line: The protective effect of NMN was accompanied by decreases in acetylation of FoxO1, but it was not obvious in Sirt1 KO mice, suggesting that the effect of NMN is mediated through activation of Sirt1.The protective effect of CR against I/R injury was not significant in cardiac-specific Sirt1 KO mice, suggesting that the protective effect of CR is in part mediated through the Nampt-Sirt1 pathway.In conclusion, exogenous application of NMN and CR protects the heart by both mimicking IPC and activating Sirt1.

View Article: PubMed Central - PubMed

Affiliation: Department of Cell Biology and Molecular Medicine, Cardiovascular Research Institute, Rutgers New Jersey Medical School, Newark, New Jersey, United States of America.

ABSTRACT
Nicotinamide phosphoribosyltransferase (Nampt), the rate-limiting enzyme for nicotinamide adenine dinucleotide (NAD+) synthesis, and Sirt1, an NAD+-dependent histone deacetylase, protect the heart against ischemia/reperfusion (I/R). It remains unknown whether Nampt mediates the protective effect of ischemic preconditioning (IPC), whether nicotinamide mononucleotide (NMN, 500 mg/kg), a product of Nampt in the NAD+ salvage pathway, mimics the effect of IPC, or whether caloric restriction (CR) upregulates Nampt and protects the heart through a Sirt1-dependent mechanism. IPC upregulated Nampt protein, and the protective effect of IPC against ischemia (30 minutes) and reperfusion (24 hours) was attenuated at both early and late phases in Nampt +/- mice, suggesting that Nampt plays an essential role in mediating the protective effect of IPC. In order to mimic the effect of Nampt, NMN was administered by intraperitoneal injection. NMN significantly increased the level of NAD+ in the heart at baseline and prevented a decrease in NAD+ during ischemia. NMN protected the heart from I/R injury when it was applied once 30 minutes before ischemia or 4 times just before and during reperfusion, suggesting that exogenous NMN protects the heart from I/R injury in both ischemic and reperfusion phases. The protective effect of NMN was accompanied by decreases in acetylation of FoxO1, but it was not obvious in Sirt1 KO mice, suggesting that the effect of NMN is mediated through activation of Sirt1. Compared to control diet (90% calories), CR (60% calories for 6 weeks) in mice led to a significant reduction in I/R injury, accompanied by upregulation of Nampt. The protective effect of CR against I/R injury was not significant in cardiac-specific Sirt1 KO mice, suggesting that the protective effect of CR is in part mediated through the Nampt-Sirt1 pathway. In conclusion, exogenous application of NMN and CR protects the heart by both mimicking IPC and activating Sirt1.

Show MeSH
Related in: MedlinePlus