| RRC ID |
86217
|
| Author |
Kosugi S, Yamaguchi S, Nishioka K, Nagahisa T, Watanabe Y, Kojima D, Kaneko K, Mitsuno R, Nakamichi R, Kawano Y, Kinouchi K, Homma K, Kanda T, Irie J, Miyashita K, Monkawa T, Yoshino J, Itoh H, Hayashi K.
|
| Title |
Vascular Endothelial NAMPT-Mediated NAD+ Biosynthesis Regulates Angiogenesis and Cardiometabolic Functions in Male Mice.
|
| Journal |
Aging Cell
|
| Abstract |
Aging is associated with metabolic dysfunction and cardiovascular abnormalities. Defective nicotinamide adenine dinucleotide (NAD+) biosynthesis correlates with aging and aging-associated complications. However, the precise molecular mechanisms linking aging-associated NAD+ deficiency to cardiometabolic dysfunction remain unclear. Herein, we examined whether nicotinamide phosphoribosyltransferase (NAMPT), a key enzyme in NAD+ biosynthesis, influences vascular endothelial function and whole-body metabolic and hemodynamic homeostasis during aging. Vascular endothelial cell-specific Nampt knockout (VeNKO) mice fed a regular chow diet exhibited no cardiometabolic abnormalities, whereas male VeNKO mice fed a high-fat diet exhibited reduced angiogenesis, resulting in impaired subcutaneous adipogenesis, impaired glucose metabolism, and hemodynamic disturbances. Mechanistically, NAMPT loss attenuated NAD+-dependent deacetylase sirtuin-1 (SIRT1) and endothelial nitric oxide synthase (eNOS) signaling, impairing angiogenesis. Aged mice exhibited endothelial NAD+ depletion driven by an imbalance between NAMPT-mediated NAD+ biosynthesis and consumption, leading to impaired eNOS signaling and associated angiogenic and cardiometabolic dysfunction, similar to that observed in VeNKO mice. Nicotinamide mononucleotide administration replenished vascular endothelial NAD+ levels, improved angiogenesis, restored subcutaneous adipose tissue volume, and ameliorated aging-associated cardiometabolic dysfunction. Collectively, our findings provide mechanistic and therapeutic insights into vascular endothelial NAMPT-NAD+-SIRT1-eNOS signaling related to aging-associated cardiometabolic disorders.
|
| Volume |
24(11)
|
| Pages |
e70222
|
| Published |
2025-11-1
|
| DOI |
10.1111/acel.70222
|
| PMID |
41021357
|
| PMC |
PMC12608088
|
| MeSH |
Angiogenesis
Animals
Cytokines* / metabolism
Endothelial Cells* / metabolism
Male
Mice
Mice, Inbred C57BL
Mice, Knockout
NAD* / biosynthesis
NAD* / metabolism
Neovascularization, Physiologic*
Nicotinamide Mononucleotide
Nicotinamide Phosphoribosyltransferase* / genetics
Nicotinamide Phosphoribosyltransferase* / metabolism
Nitric Oxide Synthase Type III / metabolism
Sirtuin 1 / metabolism
|
| IF |
7.238
|
| Resource |
| Aged mice |
|
