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1.
Circulation ; 112(22): 3415-22, 2005 Nov 29.
Artigo em Inglês | MEDLINE | ID: mdl-16301341

RESUMO

BACKGROUND: Neuronal nitric oxide synthase (NOS1) plays key cardiac physiological roles, regulating excitation-contraction coupling and exerting an antioxidant effect that maintains tissue NO-redox equilibrium. After myocardial infarction (MI), NOS1 translocates from the sarcoplasmic reticulum to the cell membrane, where it inhibits beta-adrenergic contractility, an effect previously predicted to have adverse consequences. Counter to this idea, we tested the hypothesis that NOS1 has a protective effect after MI. METHODS AND RESULTS: We studied mortality, cardiac remodeling, and upregulation of oxidative stress pathways after MI in NOS1-deficient (NOS1(-/-)) and wild-type C57BL6 (WT) mice. Compared with WT, NOS1(-/-) mice had greater mortality (hazard ratio, 2.06; P=0.036), worse left ventricular (LV) fractional shortening (19.7+/-1.5% versus 27.2+/-1.5%, P<0.05), higher LV diastolic diameter (5.5+/-0.2 versus 4.9+/-0.1 mm, P<0.05), greater residual cellular width (14.9+/-0.5 versus 12.8+/-0.5 microm, P<0.01), and equivalent beta-adrenergic hyporesponsiveness despite similar MI size. Superoxide production increased after MI in both NOS1(-/-) and WT animals, although NO increased only in WT. NADPH oxidase (P<0.05) activity increased transiently in both groups after MI, but NOS1(-/-) mice had persistent basal and post-MI elevations in xanthine oxidoreductase activity. CONCLUSIONS: Together these findings support a protective role for intact NOS1 activity in the heart after MI, despite a potential contribution to LV dysfunction through beta-adrenergic hyporesponsiveness. NOS1 deficiency contributes to an imbalance between oxidative stress and tissue NO signaling, providing a plausible mechanism for adverse consequences of NOS1 deficiency in states of myocardial injury.


Assuntos
Cardiomegalia/enzimologia , Infarto do Miocárdio/complicações , Infarto do Miocárdio/mortalidade , Óxido Nítrico Sintase Tipo I/deficiência , Animais , Cardiomegalia/etiologia , Cardiomegalia/mortalidade , Homeostase , Camundongos , Camundongos Knockout , Mortalidade , NADPH Oxidases/metabolismo , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase Tipo I/fisiologia , Oxirredução , Estresse Oxidativo , Superóxidos/metabolismo , Disfunção Ventricular Esquerda/etiologia
2.
Brain Lang ; 107(2): 167-9, 2008 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-18823655

RESUMO

Auditory word comprehension was assessed in a series of 289 acute left hemisphere stroke patients. Participants decided whether an auditorily presented word matched a picture. On different trials, words were presented with a matching picture, a semantic foil, or a phonemic foil. Participants had significantly more trouble with semantic foils across all levels of impairment.


Assuntos
Transtornos da Percepção Auditiva/fisiopatologia , Transtornos da Linguagem/fisiopatologia , Fonética , Semântica , Percepção da Fala/fisiologia , Acidente Vascular Cerebral/complicações , Idoso , Transtornos da Percepção Auditiva/etiologia , Feminino , Humanos , Transtornos da Linguagem/etiologia , Masculino
3.
Nitric Oxide ; 16(3): 331-8, 2007 May.
Artigo em Inglês | MEDLINE | ID: mdl-17307368

RESUMO

Disruption of leptin signaling in the heart may contribute to obesity-related cardiac disease, as leptin deficient (oblob) 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 oblob (n=26) and C57Bl/6 controls (n=27). Cardiac NOS1 protein abundance (P<0.01) and mRNA expression (P=0.03) were reduced in oblob (n=10 and 6, respectively), while NOS3 protein abundance and mRNA expression were unaltered. Importantly, cardiac NOS1 protein abundance was restored towards normal in oblob mice after leptin treatment (n=3; P<0.05 vs leptin untreated oblob mice). NO metabolite (nitrite and nitrate) production within the myocardium was also reduced in oblob mice (n=5; P=0.02). Furthermore, oxidative stress was increased in oblob 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 oblob 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.


Assuntos
Leptina/metabolismo , Miocárdio/enzimologia , Óxido Nítrico Sintase Tipo I/metabolismo , Obesidade/metabolismo , Estresse Oxidativo , Animais , Glutationa/metabolismo , Leptina/administração & dosagem , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Obesos , Miocárdio/citologia , NADPH Oxidases/genética , NADPH Oxidases/metabolismo , Nitratos/metabolismo , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase Tipo I/genética , Óxido Nítrico Sintase Tipo II/genética , Óxido Nítrico Sintase Tipo II/metabolismo , Óxido Nítrico Sintase Tipo III , Nitritos/metabolismo , Oxirredução , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais/fisiologia , Xantina Oxidase/genética , Xantina Oxidase/metabolismo
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