Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 5 de 5
Filtrar
1.
J Cell Mol Med ; 21(12): 3277-3287, 2017 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-28608983

RESUMEN

The use of doxorubicin (DOXO) as a chemotherapeutic drug has been hampered by cardiotoxicity leading to cardiomyopathy and heart failure. Folic acid (FA) is a modulator of endothelial nitric oxide (NO) synthase (eNOS), which in turn is an important player in diseases associated with NO insufficiency or NOS dysregulation, such as pressure overload and myocardial infarction. However, the role of FA in DOXO-induced cardiomyopathy is poorly understood. The aim of this study was to test the hypothesis that FA prevents DOXO-induced cardiomyopathy by modulating eNOS and mitochondrial structure and function. Male C57BL/6 mice were randomized to a single dose of DOXO (20 mg/kg intraperitoneal) or sham. FA supplementation (10 mg/day per oral) was started 7 days before DOXO injection and continued thereafter. DOXO resulted in 70% mortality after 10 days, with the surviving mice demonstrating a 30% reduction in stroke volume compared with sham groups. Pre-treatment with FA reduced mortality to 45% and improved stroke volume (both P < 0.05 versus DOXO). These effects of FA were underlain by blunting of DOXO-induced cardiomyocyte atrophy, apoptosis, interstitial fibrosis and impairment of mitochondrial function. Mechanistically, pre-treatment with FA prevented DOXO-induced increases in superoxide anion production by reducing the eNOS monomer:dimer ratio and eNOS S-glutathionylation, and attenuated DOXO-induced decreases in superoxide dismutase, eNOS phosphorylation and NO production. Enhancing eNOS function by restoring its coupling and subsequently reducing oxidative stress with FA may be a novel therapeutic approach to attenuate DOXO-induced cardiomyopathy.


Asunto(s)
Antioxidantes/farmacología , Cardiomiopatías/prevención & control , Cardiotónicos/farmacología , Cardiotoxicidad/prevención & control , Doxorrubicina/antagonistas & inhibidores , Doxorrubicina/toxicidad , Ácido Fólico/farmacología , Animales , Antibióticos Antineoplásicos/toxicidad , Apoptosis/efectos de los fármacos , Cardiomiopatías/inducido químicamente , Cardiomiopatías/enzimología , Cardiomiopatías/mortalidad , Cardiotoxicidad/enzimología , Cardiotoxicidad/mortalidad , Cardiotoxicidad/patología , Regulación de la Expresión Génica , Masculino , Ratones , Ratones Endogámicos C57BL , Mitocondrias/efectos de los fármacos , Mitocondrias/enzimología , Mitocondrias/patología , Miocitos Cardíacos/efectos de los fármacos , Miocitos Cardíacos/enzimología , Miocitos Cardíacos/patología , Óxido Nítrico/metabolismo , Óxido Nítrico Sintasa de Tipo III/genética , Óxido Nítrico Sintasa de Tipo III/metabolismo , Estrés Oxidativo/efectos de los fármacos , Fosforilación , Volumen Sistólico/efectos de los fármacos , Superóxido Dismutasa/genética , Superóxido Dismutasa/metabolismo , Superóxidos/antagonistas & inhibidores , Superóxidos/metabolismo , Análisis de Supervivencia
2.
Am J Physiol Endocrinol Metab ; 302(5): E481-95, 2012 Mar 01.
Artículo en Inglés | MEDLINE | ID: mdl-22167522

RESUMEN

Endothelial nitric oxide synthase (eNOS) serves as a critical enzyme in maintaining vascular pressure by producing nitric oxide (NO); hence, it has a crucial role in the regulation of endothelial function. The bioavailability of eNOS-derived NO is crucial for this function and might be affected at multiple levels. Uncoupling of eNOS, with subsequently less NO and more superoxide generation, is one of the major underlying causes of endothelial dysfunction found in atherosclerosis, diabetes, hypertension, cigarette smoking, hyperhomocysteinemia, and ischemia/reperfusion injury. Therefore, modulating eNOS uncoupling by stabilizing eNOS activity, enhancing its substrate, cofactors, and transcription, and reversing uncoupled eNOS are attractive therapeutic approaches to improve endothelial function. This review provides an extensive overview of the important role of eNOS uncoupling in the pathogenesis of endothelial dysfunction and the potential therapeutic interventions to modulate eNOS for tackling endothelial dysfunction.


Asunto(s)
Endotelio Vascular/efectos de los fármacos , Endotelio Vascular/metabolismo , Óxido Nítrico Sintasa de Tipo III/metabolismo , Óxido Nítrico/metabolismo , Enfermedades Vasculares/tratamiento farmacológico , Enfermedades Vasculares/metabolismo , Animales , Endotelio Vascular/fisiopatología , Inducción Enzimática/efectos de los fármacos , Inhibidores Enzimáticos/farmacología , Inhibidores Enzimáticos/uso terapéutico , Estabilidad de Enzimas/efectos de los fármacos , Humanos , Óxido Nítrico/agonistas , Óxido Nítrico Sintasa de Tipo III/antagonistas & inhibidores , Óxido Nítrico Sintasa de Tipo III/química , Especies Reactivas de Oxígeno/antagonistas & inhibidores , Especies Reactivas de Oxígeno/metabolismo , Células Madre/efectos de los fármacos , Células Madre/enzimología , Células Madre/metabolismo , Enfermedades Vasculares/diagnóstico , Enfermedades Vasculares/fisiopatología
3.
J Mol Cell Cardiol ; 51(4): 559-63, 2011 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-21458460

RESUMEN

Tetrahydrobiopterin (BH(4)) is an essential cofactor for aromatic amino acid hydroxylases and for all three nitric oxide synthase (NOS) isoforms. It also has a protective role in the cell as an antioxidant and scavenger of reactive nitrogen and oxygen species. Experimental studies in humans and animals demonstrate that decreased BH(4)-bioavailability, with subsequent uncoupling of endothelial NOS (eNOS) plays an important role in the pathogenesis of endothelial dysfunction, hypertension, ischemia-reperfusion injury, and pathologic cardiac remodeling. Synthetic BH(4) is clinically approved for the treatment of phenylketonuria, and experimental studies support its capacity for ameliorating cardiovascular pathophysiologies. To date, however, the translation of these studies to human patients remains limited, and early results have been mixed. In this review, we discuss the pathophysiologic role of decreased BH(4) bioavailability, molecular mechanisms regulating its metabolism, and its potential therapeutic use as well as pitfalls as an NOS-modulating drug. This article is part of a special issue entitled ''Key Signaling Molecules in Hypertrophy and Heart Failure.''


Asunto(s)
Antioxidantes/uso terapéutico , Biopterinas/análogos & derivados , Endotelio Vascular/fisiopatología , Corazón/fisiopatología , Animales , Biopterinas/biosíntesis , Biopterinas/uso terapéutico , Enfermedades Cardiovasculares/tratamiento farmacológico , Endotelio Vascular/efectos de los fármacos , Corazón/efectos de los fármacos , Humanos , Isoenzimas/metabolismo , Terapia Molecular Dirigida , Miocardio/enzimología , Óxido Nítrico Sintasa/metabolismo
SELECCIÓN DE REFERENCIAS
DETALLE DE LA BÚSQUEDA