Reduced neuronal nitric oxide synthase expression contributes to cardiac oxidative stress and nitroso-redox imbalance in ob/ob mice

Roberto M. Saraiva, Khalid M. Minhas, Meizi Zheng, Eleanor Pitz, Adriana Treuer, Daniel Gonzalez, Karl H. Schuleri, Koenraad M. Vandegaer, Lili A. Barouch, Joshua M. Hare

Research output: Contribution to journalArticle

Abstract

Disruption of leptin signaling in the heart may contribute to obesity-related cardiac disease, as leptin deficient (ob/ob) mice display cardiac hypertrophy, increased cardiac apoptosis and reduced survival. Since leptin maintains a tonic level of neuronal nitric oxide synthase (NOS1) expression in the brain, we hypothesized that leptin deficiency would decrease NOS1 cardiac expression, in turn activating xanthine oxidoreductase (XOR) and creating nitroso-redox imbalance. We studied 2- to 6-month-old ob/ob (n = 26) and C57Bl/6 controls (n = 27). Cardiac NOS1 protein abundance (P < 0.01) and mRNA expression (P = 0.03) were reduced in ob/ob (n = 10 and 6, respectively), while NOS3 protein abundance and mRNA expression were unaltered. Importantly, cardiac NOS1 protein abundance was restored towards normal in ob/ob mice after leptin treatment (n = 3; P < 0.05 vs leptin untreated ob/ob mice). NO metabolite (nitrite and nitrate) production within the myocardium was also reduced in ob/ob mice (n = 5; P = 0.02). Furthermore, oxidative stress was increased in ob/ob mice as GSH/GSSG ratio was decreased (n = 4; P = 0.02). Whereas XOR activity measured by Amplex Red fluorescence was increased (n = 8; P = 0.04), XOR and NADPH oxidase subunits protein abundance were not changed in ob/ob mice (n = 6). Leptin deficiency did not disrupt NOS1 subcellular localization, as NOS1 co-localized with ryanodine receptor but not with caveolin-3. In conclusion, leptin deficiency is linked to decreased cardiac expression of NOS1 and NO production, with a concomitant increase in XOR activity and oxidative stress, resulting in nitroso-redox imbalance. These data offer novel insights into potential mechanisms of myocardial dysfunction in obesity.

Original languageEnglish (US)
Pages (from-to)331-338
Number of pages8
JournalNitric Oxide - Biology and Chemistry
Volume16
Issue number3
DOIs
StatePublished - May 2007

Keywords

  • Free radicals
  • Heart
  • Leptin
  • NADPH
  • Nitric oxide synthase
  • Obesity
  • Oxidase
  • Xanthine oxidoreductase

ASJC Scopus subject areas

  • Biochemistry
  • Physiology
  • Clinical Biochemistry
  • Cancer Research

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  • Cite this

    Saraiva, R. M., Minhas, K. M., Zheng, M., Pitz, E., Treuer, A., Gonzalez, D., Schuleri, K. H., Vandegaer, K. M., Barouch, L. A., & Hare, J. M. (2007). Reduced neuronal nitric oxide synthase expression contributes to cardiac oxidative stress and nitroso-redox imbalance in ob/ob mice. Nitric Oxide - Biology and Chemistry, 16(3), 331-338. https://doi.org/10.1016/j.niox.2006.12.001