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Métodos Terapéuticos y Terapias MTCI
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1.
Cardiovasc Res ; 97(2): 282-92, 2013 Feb 01.
Artículo en Inglés | MEDLINE | ID: mdl-23129588

RESUMEN

AIMS: Chronic depletion of myocardial glutathione (GSH) may play a role in cardiac remodelling and dysfunction. This study examined the relationship between chronic GSH depletion and cardiac failure induced by pressure overload in mice lacking the modifier subunit (GCLM) of glutamate-cysteine ligase, the rate-limiting enzyme for GSH synthesis. In addition, we examined the association between idiopathic dilated cardiomyopathy (DCM) in humans and -588C/T polymorphism of the GCLM gene, which reduces plasma levels of GSH. METHODS AND RESULTS: Pressure overload in mice was created by transverse aortic constriction (TAC). Myocardial GSH levels after TAC in GCLM(-/-) mice were 31% of those in GCLM(+/+) mice. TAC resulted in greater heart and lung-weight-to-body-weight ratios, greater dilation and dysfunction of left ventricle, more extensive myocardial fibrosis, and worse survival in GCLM(-/-) than GCLM(+/+) mice. Supplementation of GSH diethyl ester reversed the left-ventricular dilation and contractile dysfunction and the increased myocardial fibrosis after TAC in GCLM(-/-) mice. The prevalence of -588T polymorphism of the GCLM gene was significantly higher in DCM patients (n = 205) than in age- and sex-matched control subjects (n = 253) (36 vs. 19%, respectively, P < 0.001). The -588T polymorphism increased the risk of DCM that was independent of age, diabetes, and systolic blood pressure (OR 3.13, 95% CI: 2.28-4.44; P < 0.0001). CONCLUSION: Chronic depletion of GSH exacerbates remodelling and dysfunction in the pressure-overloaded heart. The clinical relevance of this mouse model is supported by a significant association between -588T polymorphism of the GCLM gene and patients with DCM.


Asunto(s)
Glutamato-Cisteína Ligasa/fisiología , Glutatión/fisiología , Disfunción Ventricular Izquierda/etiología , Remodelación Ventricular , Animales , Calcio/metabolismo , Cardiomiopatía Dilatada/genética , Ecocardiografía , Glutamato-Cisteína Ligasa/genética , Hemodinámica , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , Miocardio/metabolismo , Estrés Oxidativo , Polimorfismo Genético , ATPasas Transportadoras de Calcio del Retículo Sarcoplásmico/fisiología
2.
Circ J ; 76(6): 1452-60, 2012.
Artículo en Inglés | MEDLINE | ID: mdl-22453003

RESUMEN

BACKGROUND: The resolution of hyperglycemia is associated with suppression of in-hospital cardiac complications in patients with acute coronary syndromes (ACS). This study evaluated carotid artery plaque echolucency using ultrasound in patients with ACS and type 2 diabetes mellitus (DM) to determine whether acarbose, an α-glucosidase inhibitor, may rapidly stabilize unstable atherosclerotic plaques. METHODS AND RESULTS: ACS patients with type 2 DM and carotid plaques (n=44) were randomly assigned to treatment with acarbose (150 or 300 mg/day, n=22) or a control group (no acarbose, n=22). Acarbose treatment was initiated within 5 days after the onset of ACS. Unstable carotid plaques were assessed by measuring plaque echolucency using carotid ultrasound with integrated backscatter (IBS) before, and at 2 weeks, 1 and 6 months after the initiation of treatment. An increase in the IBS value reflected an increase in carotid plaque echogenicity. As results, the IBS value of echolucent carotid plaques showed a significant increase at 1 month and a further increase at 6 months after treatment in the acarbose group, but there was minimal change in the control group. The increase in IBS values was significantly correlated with a decrease in C-reactive protein levels. CONCLUSIONS: Acarbose rapidly improved carotid plaque echolucency within 1 month of therapy in patients with ACS and type 2 DM.


Asunto(s)
Acarbosa/uso terapéutico , Síndrome Coronario Agudo/terapia , Arterias Carótidas/efectos de los fármacos , Enfermedades de las Arterias Carótidas/tratamiento farmacológico , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Inhibidores Enzimáticos/uso terapéutico , Inhibidores de Glicósido Hidrolasas , Hipoglucemiantes/uso terapéutico , Síndrome Coronario Agudo/sangre , Síndrome Coronario Agudo/enzimología , Adulto , Anciano , Análisis de Varianza , Biomarcadores/sangre , Proteína C-Reactiva/metabolismo , Arterias Carótidas/diagnóstico por imagen , Arterias Carótidas/patología , Enfermedades de las Arterias Carótidas/sangre , Enfermedades de las Arterias Carótidas/diagnóstico por imagen , Enfermedades de las Arterias Carótidas/patología , Grosor Intima-Media Carotídeo , Diabetes Mellitus Tipo 2/sangre , Diabetes Mellitus Tipo 2/enzimología , Femenino , Humanos , Japón , Masculino , Persona de Mediana Edad , Placa Aterosclerótica , Valor Predictivo de las Pruebas , Factores de Tiempo , Resultado del Tratamiento
3.
Exp Lung Res ; 36(4): 191-200, 2010 May.
Artículo en Inglés | MEDLINE | ID: mdl-20426527

RESUMEN

This study evaluated the hypothesis that LY374388, an inhibitor of secretory phospholipase A(2) (sPLA(2)) activity, may exert a protective effect on lipopolysaccharide (LPS)-induced acute lung injury in male C57BL/6J mice. Intratracheal administration of LPS increased histopathological changes in lung tissue, lung wet to dry ratios, and the bronchoalveolar lavage fluid levels of neutrophil numbers, sPLA(2) activity, leukotriene B(4), and thromboxane B(2). However, a simultaneous intraperitoneal treatment with LY374388 significantly attenuated these LPS-induced changes. Thus, inhibition of sPLA(2) activity significantly attenuated the acute lung injury induced by LPS. sPLA(2) played an important role in the pathogenesis of LPS-induced acute lung injury in mice.


Asunto(s)
Lesión Pulmonar Aguda/prevención & control , Ácidos Indolacéticos/uso terapéutico , Fosfolipasas A2 Secretoras/antagonistas & inhibidores , Lesión Pulmonar Aguda/patología , Animales , Líquido del Lavado Bronquioalveolar/química , Líquido del Lavado Bronquioalveolar/citología , Evaluación Preclínica de Medicamentos , Ácidos Indolacéticos/farmacología , Leucotrieno B4/análisis , Lipopolisacáridos , Pulmón/enzimología , Pulmón/patología , Masculino , Ratones , Ratones Endogámicos C57BL , Neutrófilos/citología , Peroxidasa/metabolismo , Fosfolipasas A2 Secretoras/análisis , Tromboxano B2/análisis
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