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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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The cardioprotective effect of caloric restriction depends on Sirt1 expression.Control mice (Cre(-) Sirt1flox/flox) or cardiac-specific Sirt1 heterozygous (Cre(+): Sirt1flox/+) or homozygous (Cre(+): Sirt1flox/flox) KO mice were subjected to either caloric restriction (CR) or normal diet (ND) feeding for 6 weeks and then subjected to 30 minutes of ischemia followed by 24 hours of reperfusion (I/R). A, Time course of the body weight (g) of the mice. Before the mice were subjected to CR or ND, their eating behavior was closely observed for 14 days (running period). n = 4 to 10. B, The abundance of Nampt mRNA after 6 weeks of CR or ND was evaluated with qPCR. n = 4 to 5. * p<0.05. C and D, Infarct area/AAR (C) and AAR (D) were evaluated with injection of Alcian Blue dye and TTC staining. n = 3 to 6. n.s., not significant; * p<0.05, # p<0.05 vs. Cre(-) ND group, ## p<0.01 vs. Cre(-) ND group, †† p<0.01 vs. Cre(-) CR group.
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pone-0098972-g006: The cardioprotective effect of caloric restriction depends on Sirt1 expression.Control mice (Cre(-) Sirt1flox/flox) or cardiac-specific Sirt1 heterozygous (Cre(+): Sirt1flox/+) or homozygous (Cre(+): Sirt1flox/flox) KO mice were subjected to either caloric restriction (CR) or normal diet (ND) feeding for 6 weeks and then subjected to 30 minutes of ischemia followed by 24 hours of reperfusion (I/R). A, Time course of the body weight (g) of the mice. Before the mice were subjected to CR or ND, their eating behavior was closely observed for 14 days (running period). n = 4 to 10. B, The abundance of Nampt mRNA after 6 weeks of CR or ND was evaluated with qPCR. n = 4 to 5. * p<0.05. C and D, Infarct area/AAR (C) and AAR (D) were evaluated with injection of Alcian Blue dye and TTC staining. n = 3 to 6. n.s., not significant; * p<0.05, # p<0.05 vs. Cre(-) ND group, ## p<0.01 vs. Cre(-) ND group, †† p<0.01 vs. Cre(-) CR group.

Mentions: The results presented thus far suggest that an intervention that increases the level of NAD+ and/or expression of Nampt and/or Sirt1 may be effective in reducing I/R injury in the heart. Accumulating lines of evidence show that CR protects the heart from I/R injury and that it is accompanied by increases in Sirt1 expression in the nucleus [17]–[19]. Whether CR affects Nampt expression remains to be elucidated. To this end, mice were fed a CR diet (60% of the caloric intake of mice fed ad libitum) or normal diet (ND) (90% of the caloric intake of mice fed ad libitum) for 6 weeks. The effectiveness of CR was confirmed by significant body weight loss in the CR group but not in the ND group (Figure 6A). The level of Nampt mRNA was significantly greater in the CR group than in the ND group (Figure 6B). As expected, the extent of myocardial infarction was significantly smaller in mice subjected to CR than in those subjected to ND (Figure 6C). In order to elucidate the role of Sirt1 in mediating CR-induced protection against I/R injury, control mice, cardiac-specific Sirt1 heterozygous KO mice (Sirt1flox/+- αMHC-Cre), and cardiac-specific Sirt1 homozygous KO mice (Sirt1flox/flox- αMHC-Cre) were fed with CR diet or ND for 6 weeks and then subjected to I/R (Figure 6C and 6D). The extent of the AAR was similar in all groups. Consistent with our previous report [8], the infarct was significantly larger in Sirt1flox/+- αMHC-Cre and Sirt1flox/flox- αMHC-Cre mice than in control mice fed with CR or ND. Furthermore, CR decreased the infarct size in the control group (AAR: ND = 33±1.4%, CR = 34±2.3%, n.s.; IA/AAR: ND = 31±2.1%, CR = 24±1.8%, p<0.05, n = 6), whereas CR did not decrease the infarct size in cardiac-specific Sirt1 heterozygous or homozygous knockout mice (Sirt1 hetero KO: AAR: ND = 34±1.7%, CR = 36±2.4%, n.s.; IA/AAR: ND = 39±1.9%, CR = 39±3.2%, n.s., n = 3 to 4; Sirt1 homo KO: AAR: ND = 40±1.3%, CR = 35±3.0%, n.s.; IA/AAR: ND = 52±0.2%, CR = 50±4.5%, n.s., n = 3). These results suggest that the protective effect of CR against I/R is mediated through Sirt1.


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)

The cardioprotective effect of caloric restriction depends on Sirt1 expression.Control mice (Cre(-) Sirt1flox/flox) or cardiac-specific Sirt1 heterozygous (Cre(+): Sirt1flox/+) or homozygous (Cre(+): Sirt1flox/flox) KO mice were subjected to either caloric restriction (CR) or normal diet (ND) feeding for 6 weeks and then subjected to 30 minutes of ischemia followed by 24 hours of reperfusion (I/R). A, Time course of the body weight (g) of the mice. Before the mice were subjected to CR or ND, their eating behavior was closely observed for 14 days (running period). n = 4 to 10. B, The abundance of Nampt mRNA after 6 weeks of CR or ND was evaluated with qPCR. n = 4 to 5. * p<0.05. C and D, Infarct area/AAR (C) and AAR (D) were evaluated with injection of Alcian Blue dye and TTC staining. n = 3 to 6. n.s., not significant; * p<0.05, # p<0.05 vs. Cre(-) ND group, ## p<0.01 vs. Cre(-) ND group, †† p<0.01 vs. Cre(-) CR group.
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pone-0098972-g006: The cardioprotective effect of caloric restriction depends on Sirt1 expression.Control mice (Cre(-) Sirt1flox/flox) or cardiac-specific Sirt1 heterozygous (Cre(+): Sirt1flox/+) or homozygous (Cre(+): Sirt1flox/flox) KO mice were subjected to either caloric restriction (CR) or normal diet (ND) feeding for 6 weeks and then subjected to 30 minutes of ischemia followed by 24 hours of reperfusion (I/R). A, Time course of the body weight (g) of the mice. Before the mice were subjected to CR or ND, their eating behavior was closely observed for 14 days (running period). n = 4 to 10. B, The abundance of Nampt mRNA after 6 weeks of CR or ND was evaluated with qPCR. n = 4 to 5. * p<0.05. C and D, Infarct area/AAR (C) and AAR (D) were evaluated with injection of Alcian Blue dye and TTC staining. n = 3 to 6. n.s., not significant; * p<0.05, # p<0.05 vs. Cre(-) ND group, ## p<0.01 vs. Cre(-) ND group, †† p<0.01 vs. Cre(-) CR group.
Mentions: The results presented thus far suggest that an intervention that increases the level of NAD+ and/or expression of Nampt and/or Sirt1 may be effective in reducing I/R injury in the heart. Accumulating lines of evidence show that CR protects the heart from I/R injury and that it is accompanied by increases in Sirt1 expression in the nucleus [17]–[19]. Whether CR affects Nampt expression remains to be elucidated. To this end, mice were fed a CR diet (60% of the caloric intake of mice fed ad libitum) or normal diet (ND) (90% of the caloric intake of mice fed ad libitum) for 6 weeks. The effectiveness of CR was confirmed by significant body weight loss in the CR group but not in the ND group (Figure 6A). The level of Nampt mRNA was significantly greater in the CR group than in the ND group (Figure 6B). As expected, the extent of myocardial infarction was significantly smaller in mice subjected to CR than in those subjected to ND (Figure 6C). In order to elucidate the role of Sirt1 in mediating CR-induced protection against I/R injury, control mice, cardiac-specific Sirt1 heterozygous KO mice (Sirt1flox/+- αMHC-Cre), and cardiac-specific Sirt1 homozygous KO mice (Sirt1flox/flox- αMHC-Cre) were fed with CR diet or ND for 6 weeks and then subjected to I/R (Figure 6C and 6D). The extent of the AAR was similar in all groups. Consistent with our previous report [8], the infarct was significantly larger in Sirt1flox/+- αMHC-Cre and Sirt1flox/flox- αMHC-Cre mice than in control mice fed with CR or ND. Furthermore, CR decreased the infarct size in the control group (AAR: ND = 33±1.4%, CR = 34±2.3%, n.s.; IA/AAR: ND = 31±2.1%, CR = 24±1.8%, p<0.05, n = 6), whereas CR did not decrease the infarct size in cardiac-specific Sirt1 heterozygous or homozygous knockout mice (Sirt1 hetero KO: AAR: ND = 34±1.7%, CR = 36±2.4%, n.s.; IA/AAR: ND = 39±1.9%, CR = 39±3.2%, n.s., n = 3 to 4; Sirt1 homo KO: AAR: ND = 40±1.3%, CR = 35±3.0%, n.s.; IA/AAR: ND = 52±0.2%, CR = 50±4.5%, n.s., n = 3). These results suggest that the protective effect of CR against I/R is mediated through Sirt1.

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