Navegando por Palavras-chave "xanthine oxidoreductase"

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    Reduced neuronal nitric oxide synthase expression contributes to cardiac oxidative stress and nitroso-redox imbalance in ob/ob mice
    (Elsevier B.V., 2007-05-01) 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.; Johns Hopkins Med Inst; Universidade Federal de São Paulo (UNIFESP); Univ Miami
    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.
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    Xanthine oxidoreductase inhibition causes reverse remodeling in rats with dilated cardiomyopathy
    (Lippincott Williams & Wilkins, 2006-02-03) Minhas, K. M.; Saraiva, Roberto Magalhães [UNIFESP]; Schuleri, K. H.; Lehrke, S.; Zheng, M. Z.; Saliaris, A. P.; Berry, C. E.; Vandegaer, K. M.; Li, D. C.; Hare, J. M.; Johns Hopkins Med Inst; Universidade Federal de São Paulo (UNIFESP)
    Increased reactive oxygen species (ROS) generation is implicated in cardiac remodeling in heart failure (HF). As xanthine oxidoreductase (XOR) is 1 of the major sources of ROS, we tested whether XOR inhibition could improve cardiac performance and induce reverse remodeling in a model of established HF, the spontaneously hypertensive/HF (SHHF) rat. We randomized Wistar Kyoto (WKY, controls, 18 to 21 months) and SHHF ( 19 to 21 months) rats to oxypurinol (1 mmol/L; n = 4 and n = 15, respectively) or placebo (n = 3 and n = 10, respectively) orally for 4 weeks. At baseline, SHHF rats had decreased fractional shortening (FS) (31 +/- 3% versus 67 +/- 3% in WKY, P < 0.0001) and increased left-ventricular (LV) end-diastolic dimension (9.7 +/- 0.2 mm versus 7.0 +/- 0.4 mm in WKY, P < 0.0001). Whereas placebo and oxypurinol did not change cardiac architecture in WKY, oxypurinol attenuated decreased FS and elevated LV end-diastolic dimension, LV end-systolic dimension, and LV mass in SHHF. Increased myocyte width in SHHF was reduced by oxypurinol. Additionally, fetal gene activation, altered calcium cycling proteins, and upregulated phospho-extracellular signal-regulated kinase were restored toward normal by oxypurinol (P < 0.05 versus placebo-SHHF). Importantly, SHHF rats exhibited increased XOR mRNA expression and activity, and oxypurinol treatment reduced XOR activity and superoxide production toward normal, but not expression. On the other hand, NADPH oxidase activity remained unchanged, despite elevated subunit protein abundance in treated and untreated SHHF rats. Together these data demonstrate that chronic XOR inhibition restores cardiac structure and function and offsets alterations in fetal gene expression/Ca2+ handling pathways, supporting the idea that inhibiting XOR-derived oxidative stress substantially improves the HF phenotype.