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

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

Author Saraiva, Roberto M. Google Scholar
Minhas, Khalid M. Google Scholar
Zheng, Meizi Google Scholar
Pitz, Eleanor Google Scholar
Treuer, Adriana Google Scholar
Gonzalez, Daniel Google Scholar
Schuleri, Karl H. Google Scholar
Vandegaer, Koenraad M. Google Scholar
Barouch, Lili A. Google Scholar
Hare, Joshua M. Google Scholar
Institution Johns Hopkins Med Inst
Universidade Federal de São Paulo (UNIFESP)
Univ Miami
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 1 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 C57B1/6 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 NOSI 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. (c) 2006 Elsevier Inc. All rights reserved.
Keywords obesity
heart
free radicals
leptin
nitric oxide synthase
xanthine oxidoreductase
NADPH
oxidase
Language English
Date 2007-05-01
Published in Nitric Oxide-biology and Chemistry. San Diego: Academic Press Inc Elsevier Science, v. 16, n. 3, p. 331-338, 2007.
ISSN 1089-8603 (Sherpa/Romeo, impact factor)
Publisher Elsevier B.V.
Extent 331-338
Origin http://dx.doi.org/10.1016/j.niox.2006.12.001
Access rights Closed access
Type Article
Web of Science ID WOS:000245930000003
URI http://repositorio.unifesp.br/handle/11600/29706

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