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

NMN administration reduces I/R injury.Either NMN (500 mg/kg per injection) or vehicle (PBS) was administered (i.p. injection) to mice according to one of four different protocols (Figure S4 in File S1), the mice were subjected to I/R, and the extent of I/R injury was evaluated with TTC staining. In A-H, control mice were used. NMN or PBS was injected once 12 hours before I/R (A and B), once 30 minutes before I/R (C and D), once just before reperfusion (E and F) or once just before reperfusion and 3 more times every 6 hours thereafter (G and H). In I and J, NMN or PBS was injected once 30 minutes before I/R in Nampt+/− mice. Infarct area/AAR (A, C, E, G, and I) and AAR (B, D, F, H, and J) are shown. n = 4 to 7. 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-g004: NMN administration reduces I/R injury.Either NMN (500 mg/kg per injection) or vehicle (PBS) was administered (i.p. injection) to mice according to one of four different protocols (Figure S4 in File S1), the mice were subjected to I/R, and the extent of I/R injury was evaluated with TTC staining. In A-H, control mice were used. NMN or PBS was injected once 12 hours before I/R (A and B), once 30 minutes before I/R (C and D), once just before reperfusion (E and F) or once just before reperfusion and 3 more times every 6 hours thereafter (G and H). In I and J, NMN or PBS was injected once 30 minutes before I/R in Nampt+/− mice. Infarct area/AAR (A, C, E, G, and I) and AAR (B, D, F, H, and J) are shown. n = 4 to 7. n.s., not significant; * p<0.05, ** p<0.01.

Mentions: The data shown above suggest that decreases in the NAD+ content during myocardial ischemia can be reversed by the administration of NMN. We hypothesized that NMN may mimic the effect of IPC. To test this hypothesis, we injected NMN (500 mg/kg, i.p., once or 4 times) into mice, and its effect upon I/R injury was investigated. In order to explore the timing of the maximum effect of NMN in reducing the infarct size, NMN was applied with 4 different protocols: group 1, once 12 hours before ischemia; group 2, once 30 min before ischemia; group 3, once immediately before reperfusion; group 4, once immediately before reperfusion and 3 times thereafter at 6 hours intervals (Figure S4 in File S1). The extent of the AAR was not significantly affected by NMN in any group. While NMN administration 12 hours before ischemia and immediately before reperfusion (group 1 and group 3) did not cause any significant reduction in infarct size (group 1: AAR: NMN = 33±0.6%, vehicle = 32±1.2%, n.s.; IA/AAR: NMN = 36±4.7%, vehicle = 37±1.3%, n.s., n = 5, group 3: AAR: NMN = 26±0.5%, vehicle = 27±1.0%, n.s.; IA/AAR: NMN = 37±1.4%, vehicle = 34±2.2%, n.s., n = 4), NMN administration 30 min before ischemia and repetitive administration just before and during reperfusion (group 2 and group 4) reduced the infarct size by 44% and 29%, respectively, compared to their respective vehicle groups (group 2: AAR: NMN = 30±1.9%, vehicle = 29±1.7%, n.s.; IA/AAR: NMN = 23±2.9%, vehicle = 41±2.6%, p<0.01, n = 6 to 7, group 4: AAR: NMN = 32±2.7%, vehicle = 35±4.2%, n.s.; IA/AAR: NMN = 35±4.4%, vehicle = 49±3.2%, p<0.05, n = 4) (Figure 4A-H and Figure S5 in File S1). These results suggest that exogenous NMN has a timing-dependent ability to reduce the infarct size in response to I/R. Considering the transient action of NMN (Figure 3A), the fact that group 2, but not group 3, exhibited protection suggests that NMN action is more critical for protection during ischemia than during the early phase of reperfusion. However, the fact that group 4 also exhibited protection suggests that continuous elevation of NMN throughout reperfusion for 24 hours can also protect the heart from I/R injury. Taken together, the data suggest that exogenous application of NMN can mimic the effect of IPC.


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)

NMN administration reduces I/R injury.Either NMN (500 mg/kg per injection) or vehicle (PBS) was administered (i.p. injection) to mice according to one of four different protocols (Figure S4 in File S1), the mice were subjected to I/R, and the extent of I/R injury was evaluated with TTC staining. In A-H, control mice were used. NMN or PBS was injected once 12 hours before I/R (A and B), once 30 minutes before I/R (C and D), once just before reperfusion (E and F) or once just before reperfusion and 3 more times every 6 hours thereafter (G and H). In I and J, NMN or PBS was injected once 30 minutes before I/R in Nampt+/− mice. Infarct area/AAR (A, C, E, G, and I) and AAR (B, D, F, H, and J) are shown. n = 4 to 7. 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-g004: NMN administration reduces I/R injury.Either NMN (500 mg/kg per injection) or vehicle (PBS) was administered (i.p. injection) to mice according to one of four different protocols (Figure S4 in File S1), the mice were subjected to I/R, and the extent of I/R injury was evaluated with TTC staining. In A-H, control mice were used. NMN or PBS was injected once 12 hours before I/R (A and B), once 30 minutes before I/R (C and D), once just before reperfusion (E and F) or once just before reperfusion and 3 more times every 6 hours thereafter (G and H). In I and J, NMN or PBS was injected once 30 minutes before I/R in Nampt+/− mice. Infarct area/AAR (A, C, E, G, and I) and AAR (B, D, F, H, and J) are shown. n = 4 to 7. n.s., not significant; * p<0.05, ** p<0.01.
Mentions: The data shown above suggest that decreases in the NAD+ content during myocardial ischemia can be reversed by the administration of NMN. We hypothesized that NMN may mimic the effect of IPC. To test this hypothesis, we injected NMN (500 mg/kg, i.p., once or 4 times) into mice, and its effect upon I/R injury was investigated. In order to explore the timing of the maximum effect of NMN in reducing the infarct size, NMN was applied with 4 different protocols: group 1, once 12 hours before ischemia; group 2, once 30 min before ischemia; group 3, once immediately before reperfusion; group 4, once immediately before reperfusion and 3 times thereafter at 6 hours intervals (Figure S4 in File S1). The extent of the AAR was not significantly affected by NMN in any group. While NMN administration 12 hours before ischemia and immediately before reperfusion (group 1 and group 3) did not cause any significant reduction in infarct size (group 1: AAR: NMN = 33±0.6%, vehicle = 32±1.2%, n.s.; IA/AAR: NMN = 36±4.7%, vehicle = 37±1.3%, n.s., n = 5, group 3: AAR: NMN = 26±0.5%, vehicle = 27±1.0%, n.s.; IA/AAR: NMN = 37±1.4%, vehicle = 34±2.2%, n.s., n = 4), NMN administration 30 min before ischemia and repetitive administration just before and during reperfusion (group 2 and group 4) reduced the infarct size by 44% and 29%, respectively, compared to their respective vehicle groups (group 2: AAR: NMN = 30±1.9%, vehicle = 29±1.7%, n.s.; IA/AAR: NMN = 23±2.9%, vehicle = 41±2.6%, p<0.01, n = 6 to 7, group 4: AAR: NMN = 32±2.7%, vehicle = 35±4.2%, n.s.; IA/AAR: NMN = 35±4.4%, vehicle = 49±3.2%, p<0.05, n = 4) (Figure 4A-H and Figure S5 in File S1). These results suggest that exogenous NMN has a timing-dependent ability to reduce the infarct size in response to I/R. Considering the transient action of NMN (Figure 3A), the fact that group 2, but not group 3, exhibited protection suggests that NMN action is more critical for protection during ischemia than during the early phase of reperfusion. However, the fact that group 4 also exhibited protection suggests that continuous elevation of NMN throughout reperfusion for 24 hours can also protect the heart from I/R injury. Taken together, the data suggest that exogenous application of NMN can mimic the effect of IPC.

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