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Mecanismo novedoso para la disfunción endotelial: desregulación de la dimetilarginina y la dimetilaminohidrolasa
1Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, CA, USA.
Circulation
|June 22, 1999
Resumen
La reducción de la degradación de la dimetilarginina asimétrica (ADMA), un inhibidor de la óxido nítrico sintasa (NOS), contribuye a la disfunción endotelial en la hipercolesterolemia. Este estudio investigó la acumulación de ADMA y la actividad de la dimetilarginina dimetilaminohidrolasa (DDAH) en células endoteliales y conejos.
Área de la Ciencia:
- Investigaciones Cardiovasculares Investigación Cardiovascular Investigaciones Cardiovasculares
- Biología endotelial Biología endotelial.
- Trastornos metabólicos Los trastornos metabólicos son trastornos metabólicos que se producen en el cuerpo.
Sus antecedentes:
- La dimetilarginina asimétrica (ADMA) inhibe la síntasa de óxido nítrico (NOS), y el ADMA plasmático elevado está relacionado con la hipercolesterolemia y la aterosclerosis.
- Se supone que la reducción de la degradación de ADMA contribuye a la acumulación de ADMA en estas condiciones.
Objetivo del estudio:
- Para investigar los efectos del LDL oxidado (oxLDL) y el factor de necrosis tumoral-alfa (TNF-alfa) en la acumulación de ADMA en las células endoteliales.
- Para examinar el impacto de estos factores en la actividad de la dimetilarginina dimetilaminohidrolasa (DDAH), la enzima responsable de la degradación de ADMA.
- Para evaluar la actividad de DDAH in vivo en un modelo de conejo de hipercolesterolemia.
Principales métodos:
- Las células endoteliales de la vena umbilical humana transformadas (ECV304) fueron tratadas con LDL nativo, oxLDL o TNF-alfa.
- Los niveles de ADMA en el medio acondicionado se midieron utilizando cromatografía líquida de alto rendimiento.
- La expresión de DDAH fue evaluada por Western blotting, y la actividad de DDAH fue determinada por la formación de L-citrulina.
- Los conejos blancos de Nueva Zelanda fueron alimentados con una dieta normal o alta en colesterol para inducir hipercolesterolemia.
Principales resultados:
- La LDL oxidada y el TNF-alfa aumentaron significativamente los niveles de ADMA en las células endoteliales.
- Este aumento se atribuyó a la reducción de la actividad de DDAH, no a la expresión alterada de DDAH.
- La hipercolesterolemia en conejos condujo a una actividad DDAH significativamente reducida en la aorta, los riñones y el hígado.
Conclusiones:
- La disfunción endotelial en la hipercolesterolemia puede ser el resultado de una deterioración de la degradación de ADMA debido a la reducción de la actividad de DDAH.
- Estos hallazgos resaltan el papel de la desregulación de la DDAH en la fisiopatología de los problemas vasculares relacionados con la hipercolesterolemia.
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