Title: Oral nitrite restores age-dependent phenotypes in eNOS-null mice.
Authors: Tenopoulou, Margarita; Doulias, Paschalis-Thomas; Nakamoto, Kent; Berrios, Kiara; Zura, Gabriella; Li, Chenxi; Faust, Michael; Yakovishina, Veronika; Evans, Perry; Tan, Lu; Bennett, Michael J; Snyder, Nathaniel W; Quinn 3rd, William J; Baur, Joseph A; Atochin, Dmitriy N; Huang, Paul L; Ischiropoulos, Harry
Published In JCI Insight, (2018 08 23)
Abstract: Alterations in the synthesis and bioavailability of NO are central to the pathogenesis of cardiovascular and metabolic disorders. Although endothelial NO synthase-derived (eNOS-derived) NO affects mitochondrial long-chain fatty acid β-oxidation, the pathophysiological significance of this regulation remains unclear. Accordingly, we determined the contributions of eNOS/NO signaling in the adaptive metabolic responses to fasting and in age-induced metabolic dysfunction. Four-month-old eNOS-/- mice are glucose intolerant and exhibit serum dyslipidemia and decreased capacity to oxidize fatty acids. However, during fasting, eNOS-/- mice redirect acetyl-CoA to ketogenesis to elevate circulating levels of β-hydroxybutyrate similar to wild-type mice. Treatment of 4-month-old eNOS-/- mice with nitrite for 10 days corrected the hypertension and serum hyperlipidemia and normalized the rate of fatty acid oxidation. Fourteen-month-old eNOS-/- mice exhibited metabolic derangements, resulting in reduced utilization of fat to generate energy, lower resting metabolic activity, and diminished physical activity. Seven-month administration of nitrite to eNOS-/- mice reversed the age-dependent metabolic derangements and restored physical activity. While the eNOS/NO signaling is not essential for the metabolic adaptation to fasting, it is critical for regulating systemic metabolic homeostasis in aging. The development of age-dependent metabolic disorder is prevented by low-dose replenishment of bioactive NO.
PubMed ID: 30135317
MeSH Terms: Administration, Oral; Aging/drug effects; Aging/metabolism*; Animals; Disease Models, Animal; Drug Evaluation, Preclinical; Fasting/metabolism; Homeostasis/drug effects*; Humans; Hyperlipidemias/drug therapy; Hyperlipidemias/genetics; Hyperlipidemias/metabolism; Hypertension/drug therapy; Hypertension/genetics; Hypertension/metabolism; Male; Mice; Mice, Knockout; Nitric Oxide Synthase Type III/deficiency*; Nitric Oxide Synthase Type III/genetics; Nitric Oxide/metabolism; Signal Transduction/drug effects; Sodium Nitrite/administration & dosage*; Time Factors; Treatment Outcome