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

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Saraiva, Roberto M. [UNIFESP]
Minhas, Khalid M.
Zheng, Meizi
Pitz, Eleanor
Treuer, Adriana
Gonzalez, Daniel
Schuleri, Karl H.
Vandegaer, Koenraad M.
Barouch, Lili A.
Hare, Joshua M.
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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.
Nitric Oxide-biology and Chemistry. San Diego: Academic Press Inc Elsevier Science, v. 16, n. 3, p. 331-338, 2007.