Monocyte-derived extracellular Nampt-dependent biosynthesis of NAD+ protects the heart against pressure overload
| Autor: | Masamichi Yano, Chizuru Yabumoto, Toru Oka, Yoko Kudo-Sakamoto, Hiroshi Akazawa, Yasushi Sakata, Jun-ichi Suzuki, Hiroki Yagi, Jong-Kook Lee, Yu Shimizu, Issei Komuro, Takehiro Kamo, Atsuhiko T. Naito |
|---|---|
| Rok vydání: | 2015 |
| Předmět: |
Male
medicine.medical_specialty Nicotinamide phosphoribosyltransferase Nicotinamide adenine dinucleotide Protective Agents Article Monocytes Mice chemistry.chemical_compound Sirtuin 1 Internal medicine Extracellular medicine Animals Nicotinamide Phosphoribosyltransferase Nicotinamide Mononucleotide Nicotinamide mononucleotide Pressure overload Multidisciplinary biology Myocardium Heart NAD Up-Regulation Cell biology Mice Inbred C57BL Endocrinology chemistry biology.protein Cytokines NAD+ kinase Deacetylase activity |
| Zdroj: | Scientific Reports |
| ISSN: | 2045-2322 |
| DOI: | 10.1038/srep15857 |
| Popis: | Nicotinamide phosphoribosyltransferase (Nampt) catalyzes the rate-limiting step in the salvage pathway for nicotinamide adenine dinucleotide (NAD+) biosynthesis and thereby regulates the deacetylase activity of sirtuins. Here we show accommodative regulation of myocardial NAD+ by monocyte-derived extracellular Nampt (eNampt), which is essential for hemodynamic compensation to pressure overload. Although intracellular Nampt (iNampt) expression was decreased in pressure-overloaded hearts, myocardial NAD+ concentration and Sirt1 activity were preserved. In contrast, iNampt was up-regulated in spleen and monocytes and circulating eNampt protein and nicotinamide mononucleotide (NMN), a key precursor of NAD+, were significantly increased. Pharmacological inhibition of Nampt by FK866 or depletion of monocytes/macrophages by clodronate liposomes disrupted the homeostatic mechanism of myocardial NAD+ levels and NAD+-dependent Sirt1 activity, leading to susceptibility to cardiomyocyte apoptosis and cardiac decompensation in pressure-overloaded mice. These biochemical and hemodynamic defects were prevented by systemic administration of NMN. Our studies uncover a crucial role of monocyte-derived eNampt in myocardial adaptation to pressure overload and highlight a potential intervention controlling myocardial NAD+ against heart failure. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|