Abstract 15804: Protective Effect of Nicotinamide Phosphoribosyltransferase (Nampt) against Cardiac Pressure Overload
Background: Nicotinamide adenine dinucleotide (NAD+) participates in a wide variety of cellular functions in the heart as an electron-transferring molecule in the electron transport chain for ATP synthesis and a substrate for sirtuins, a family of enzymes involved in metabolism and aging. Nicotinamide phosphoribosyltransferase (Nampt), a rate-limiting enzyme in the salvage pathway for NAD+ biosynthesis, plays a key role in mediating NAD+ synthesis in cardiomyocytes (CMs). Although expression of Nampt is downregulated in response to stress in CMs, the role of Nampt in mediating cell survival and cardiac function remains to be elucidated in the failing heart in vivo.
Methods and Results: Both NAD+ and NADH contents and the NAD+/NADH ratio in the heart were significantly decreased in wild type mice (WT) subjected to transverse aortic constriction (TAC) for 4 weeks (NAD+: sham=268±20, TAC=195±11 pmol/mg tissue, p=0.01; NADH: sham=224±32, TAC=96±8 pmol/mg tissue, p<0.01; NAD+/NADH ratio: sham=1.27±0.19, TAC=2.09±0.24, p<0.05; n=4-5). The NAD+ content in the heart was significantly lower in Nampt heterozygous KO mice (Nampt+/-) (NAD+: WT=320±24, Nampt+/-=257±6 pmol/mg tissue, p<0.05; NADH: WT=151±13, Nampt+/-=176±8 pmol/mg tissue, n.s.; NAD+/NADH ratio: WT=2.16±0.26, Nampt+/-=1.47±0.06, n.s.; n=3-5). After TAC (4 weeks), left ventricular weight /tibial length (LVW/TL) in Nampt+/- was not significantly different from that in WT (WT=11.1±0.6 mg/mm; Nampt+/-=11.4±0.7 mg/mm, n.s). However, left ventricular ejection fraction (EF) was significantly reduced in Nampt+/- (WT=66.6±3.0%, Nampt+/-=51.8±3.4%, p<0.01, n=5-8). There was no significant difference in CM cross-sectional area between WT and Nampt+/-, but there was a tendency for increased fibrosis (WT=0.8±0.6%; Nampt+/-=3.0±0.7%, p=0.05) and an increased number of TdT-mediated dUTP nick-end labeling (TUNEL) positive cells in Nampt+/- (WT=0.10±0.09%; Nampt+/-=0.53±0.15%, p< 0.05, n=3).
Conclusions: These results suggest that endogenous Nampt plays a critical role in regulating NAD+ content and protecting the heart from apoptosis and eventual cardiac dysfunction during pressure overload. Furthermore, decreases in NAD+ during pressure overload are detrimental for the heart.
- © 2012 by American Heart Association, Inc.