Limits...
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.

Show MeSH

Related in: MedlinePlus

NAD+ content in the heart is reduced in Nampt +/− mice.A and B, Heart homogenates were prepared from Nampt +/− mice and their wild-type (Wt) littermates. A, NAD+ and NADH contents. B, NAD+/NADH ratio. C-E, Mice were subjected to sham procedure or IPC, as shown in Figure 1A. Mice were then subjected to either 30 minutes ischemia or sham operation 5 minutes after the sham procedure or either 5 minutes or 24 hours after IPC. C, NAD+ contents. D, NADH contents. E, NAD+/NADH ratio. In A-E, n = 4. n.s., not significant; * p<0.05, ** p<0.01.
© Copyright Policy
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4048236&req=5

pone-0098972-g002: NAD+ content in the heart is reduced in Nampt +/− mice.A and B, Heart homogenates were prepared from Nampt +/− mice and their wild-type (Wt) littermates. A, NAD+ and NADH contents. B, NAD+/NADH ratio. C-E, Mice were subjected to sham procedure or IPC, as shown in Figure 1A. Mice were then subjected to either 30 minutes ischemia or sham operation 5 minutes after the sham procedure or either 5 minutes or 24 hours after IPC. C, NAD+ contents. D, NADH contents. E, NAD+/NADH ratio. In A-E, n = 4. n.s., not significant; * p<0.05, ** p<0.01.

Mentions: We evaluated the NAD+ and NADH content in the hearts of Nampt +/− mice at baseline (Figure 2A and 2B). Although the NADH content in the hearts of Nampt +/− mice was not significantly different from that in wild-type littermates, the NAD+ content and NAD+/NADH ratio at baseline were significantly lower in Nampt +/− mice than in wild-type littermates, suggesting that endogenous Nampt plays an essential role in maintaining the NAD+ level and NAD+/NADH in the mouse heart. We have shown previously that prolonged myocardial ischemia time-dependently downregulates Nampt in the mouse heart [13]. Although the NAD+ content and NAD+/NADH ratio in the mouse heart after 30 min of ischemia were decreased without IPC, they were preserved when ischemia was applied either 5 min or 24 hours after IPC (Figure S3 in File S1, Figure 2C-E). The NADH content did not change after 30 min of ischemia with or without IPC. These results suggest that IPC acts to maintain the level of NAD+ and the NAD+/NADH ratio during myocardial ischemia.


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 in the heart is reduced in Nampt +/− mice.A and B, Heart homogenates were prepared from Nampt +/− mice and their wild-type (Wt) littermates. A, NAD+ and NADH contents. B, NAD+/NADH ratio. C-E, Mice were subjected to sham procedure or IPC, as shown in Figure 1A. Mice were then subjected to either 30 minutes ischemia or sham operation 5 minutes after the sham procedure or either 5 minutes or 24 hours after IPC. C, NAD+ contents. D, NADH contents. E, NAD+/NADH ratio. In A-E, n = 4. n.s., not significant; * p<0.05, ** p<0.01.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4048236&req=5

pone-0098972-g002: NAD+ content in the heart is reduced in Nampt +/− mice.A and B, Heart homogenates were prepared from Nampt +/− mice and their wild-type (Wt) littermates. A, NAD+ and NADH contents. B, NAD+/NADH ratio. C-E, Mice were subjected to sham procedure or IPC, as shown in Figure 1A. Mice were then subjected to either 30 minutes ischemia or sham operation 5 minutes after the sham procedure or either 5 minutes or 24 hours after IPC. C, NAD+ contents. D, NADH contents. E, NAD+/NADH ratio. In A-E, n = 4. n.s., not significant; * p<0.05, ** p<0.01.
Mentions: We evaluated the NAD+ and NADH content in the hearts of Nampt +/− mice at baseline (Figure 2A and 2B). Although the NADH content in the hearts of Nampt +/− mice was not significantly different from that in wild-type littermates, the NAD+ content and NAD+/NADH ratio at baseline were significantly lower in Nampt +/− mice than in wild-type littermates, suggesting that endogenous Nampt plays an essential role in maintaining the NAD+ level and NAD+/NADH in the mouse heart. We have shown previously that prolonged myocardial ischemia time-dependently downregulates Nampt in the mouse heart [13]. Although the NAD+ content and NAD+/NADH ratio in the mouse heart after 30 min of ischemia were decreased without IPC, they were preserved when ischemia was applied either 5 min or 24 hours after IPC (Figure S3 in File S1, Figure 2C-E). The NADH content did not change after 30 min of ischemia with or without IPC. These results suggest that IPC acts to maintain the level of NAD+ and the NAD+/NADH ratio during myocardial ischemia.

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