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Oral nitrite restores age-dependent phenotypes in eNOS-null mice
Journal article   Open access   Peer reviewed

Oral nitrite restores age-dependent phenotypes in eNOS-null mice

Margarita Tenopoulou, Paschalis-Thomas Doulias, Kent Nakamoto, Kiara Berrios, Gabriella Zura, Chenxi Li, Michael Faust, Veronika Yakovishina, Perry Evans, Lu Tan, …
JCI insight, v 3(16)
23 Aug 2018
DOI: https://doi.org/10.1172/jci.insight.122156
PMID: 30135317
Featured in Collection :   UN Sustainable Development Goals @ Drexel
url
https://doi.org/10.1172/jci.insight.122156View
Published, Version of Record (VoR)Open Access (License Unspecified),  Open

Abstract

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 - metabolism Nitric Oxide Synthase Type III - deficiency Nitric Oxide Synthase Type III - genetics Signal Transduction - drug effects Sodium Nitrite - administration & dosage Time Factors Treatment Outcome
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.

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11 citations in Web of Science
13 citations in Scopus

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UN Sustainable Development Goals (SDGs)

This publication has contributed to the advancement of the following goals:

#3 Good Health and Well-Being

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Collaboration types
Domestic collaboration
Web of Science research areas
Medicine, Research & Experimental
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