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.
Highlights
Ischemia followed by reperfusion (I/R) in the heart is a lifethreatening event, and myocardial damage induced by I/R is an important cause of heart failure in patients [1]
Nicotinamide phosphoribosyltransferase (Nampt) is upregulated by ischemic preconditioning We examined whether expression of Nampt, the rate-limiting enzyme for NAD+ synthesis in the heart, is regulated by IPC
Using Nampt +/2 mice, we demonstrated that Nampt plays an essential role in mediating the cardioprotective effect of IPC against I/R
Summary
Ischemia followed by reperfusion (I/R) in the heart is a lifethreatening event, and myocardial damage induced by I/R is an important cause of heart failure in patients [1]. Shortly after exposure to ischemia or hypoxia, adenosine triphosphate (ATP) contents rapidly decrease in cardiomyocytes. In order to survive during ischemia or hypoxia, cardiomyocytes switch their metabolism from an aerobic mechanism to an anaerobic one, namely, from fatty acid oxidation to glycolysis [2], and activate autophagy, a self-eating mechanism, to salvage ATP [3]. Cytochrome c release from mitochondria triggers apoptosis, while mitochondrial permeability transition pore opening is followed by depletion of ATP, decreases in the intracellular pH, increases in Ca2+ overload, and eventual necrosis in cardiomyocytes [4]. Surviving cardiomyocytes suffer from endoplasmic reticulum (ER) stress or oxidative stress, both of which cause cellular malfunctions. I/R is a series of events that induce nearly unavoidable cell death and serious malfunction in cardiomyocytes, and despite intensive investigations in the field, interventions with clinically proven efficacy remain to be developed
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