Nicotinamide Phosphoribosyltransferase Regulates Cell Survival Through NAD + Synthesis in Cardiac Myocytes
- 28 August 2009
- journal article
- research article
- Published by Ovid Technologies (Wolters Kluwer Health) in Circulation Research
- Vol. 105 (5), 481-491
- https://doi.org/10.1161/circresaha.109.203703
Abstract
Rationale: NAD+ acts not only as a cofactor for cellular respiration but also as a substrate for NAD+-dependent enzymes, such as Sirt1. The cellular NAD+ synthesis is regulated by both the de novo and the salvage pathways. Nicotinamide phosphoribosyltransferase (Nampt) is a rate-limiting enzyme in the salvage pathway. Objective: Here we investigated the role of Nampt in mediating NAD+ synthesis in cardiac myocytes and the function of Nampt in the heart in vivo. Methods and Results: Expression of Nampt in the heart was significantly decreased by ischemia, ischemia/reperfusion and pressure overload. Upregulation of Nampt significantly increased NAD+ and ATP concentrations, whereas downregulation of Nampt significantly decreased them. Downregulation of Nampt increased caspase 3 cleavage, cytochrome c release, and TUNEL-positive cells, which were inhibited in the presence of Bcl-xL, but did not increase hairpin 2–positive cells, suggesting that endogenous Nampt negatively regulates apoptosis but not necrosis. Downregulation of Nampt also impaired autophagic flux, suggesting that endogenous Nampt positively regulates autophagy. Cardiac-specific overexpression of Nampt in transgenic mice increased NAD+ content in the heart, prevented downregulation of Nampt, and reduced the size of myocardial infarction and apoptosis in response to prolonged ischemia and ischemia/reperfusion. Conclusions: Nampt critically regulates NAD+ and ATP contents, thereby playing an essential role in mediating cell survival by inhibiting apoptosis and stimulating autophagic flux in cardiac myocytes. Preventing downregulation of Nampt inhibits myocardial injury in response to myocardial ischemia and reperfusion. These results suggest that Nampt is an essential gatekeeper of energy status and survival in cardiac myocytes.Keywords
This publication has 29 references indexed in Scilit:
- A role for the NAD-dependent deacetylase Sirt1 in the regulation of autophagyProceedings of the National Academy of Sciences of the United States of America, 2008
- Nutrient-Sensitive Mitochondrial NAD+ Levels Dictate Cell SurvivalCell, 2007
- Protein Turnover Via Autophagy: Implications for MetabolismAnnual Review of Nutrition, 2007
- The regulation of nicotinamide adenine dinucleotide biosynthesis by Nampt/PBEF/visfatin in mammalsCurrent Opinion in Gastroenterology, 2007
- Sirtuins as potential targets for metabolic syndromeNature, 2006
- Induction of Autophagy in Axonal Dystrophy and DegenerationJournal of Neuroscience, 2006
- Involvement of poly(ADP-ribose) polymerase activity in regulating Chk1-dependent apoptotic cell deathDNA Repair, 2005
- Visfatin: A Protein Secreted by Visceral Fat That Mimics the Effects of InsulinScience, 2005
- Chelerythrine Rapidly Induces Apoptosis through Generation of Reactive Oxygen Species in Cardiac MyocytesJournal of Molecular and Cellular Cardiology, 2001
- Connexin 43 hemichannels mediate Ca2+‐regulated transmembrane NAD+ fluxes in intact cellsThe FASEB Journal, 2000