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La activación del receptor nuclear Nur77 por la 6-mercaptopurina protege contra la formación de neointima
Nuno M M Pires1, Thijs W H Pols, Margreet R de Vries
1Gaubius Laboratory, TNO-Quality of Life, Leiden, The Netherlands.
Circulation
|January 24, 2007
Resumen
La 6-mercaptopurina (6-MP) inhibe la proliferación y la restenosis de las células del músculo liso vascular mediante la activación del receptor nuclear Nur77. Esta activación reduce la síntesis de ADN y la formación de neointima, ofreciendo un tratamiento potencial para la restenosis del stent.
Área de la Ciencia:
- Biología Cardiovascular Biología Cardiovascular
- La medicina molecular es una medicina molecular.
- Farmacología Farmacología.
Sus antecedentes:
- La restenosis, una complicación de las intervenciones coronarias percutáneas, implica una proliferación excesiva de células del músculo liso vascular (SMC).
- El receptor nuclear Nur77 ha sido identificado como un factor protector contra la formación de lesiones ricas en SMC.
- Se sabe que la 6-mercaptopurina (6-MP) mejora la actividad de Nur77.
Objetivo del estudio:
- Investigar la hipótesis de que el 6-MP inhibe la formación de neointima a través de la activación de Nur77.
- Aclarar los mecanismos moleculares por los cuales el 6-MP afecta la proliferación de SMC y la formación de neointima en relación con la actividad de Nur77.
Principales métodos:
- Evaluó el efecto de 6-MP en la actividad de Nur77 y la síntesis de ADN en SMCs cultivadas, utilizando ARN pequeño interferente para la knockdown de Nur77.
- Utilizó un modelo murino de formación de neointima inducida por el manguito para estudiar los efectos in vivo de 6-MP.
- 6-MP administrado localmente a través de manguitos de liberación de fármacos en ratones salvajes y ratones Nur77-transgénicos.
Principales resultados:
- 6-MP aumentó la actividad de Nur77 en SMCs cultivadas, reduciendo la síntesis de ADN, un efecto parcialmente revertido por la knockdown de Nur77.
- In vivo, la administración local de 6-MP inhibió significativamente la formación de neointima en ratones de tipo salvaje al reducir el antígeno nuclear celular proliferante y aumentar los niveles de p27 (Kip1).
- Se observó una mayor inhibición de la formación de neointima en ratones con sobreexpresión de Nur77, mientras que 6-MP no tuvo ningún efecto en ratones con Nur77 dominante-negativo, lo que confirma el papel de Nur77.
Conclusiones:
- 6-MP protege contra la proliferación de SMC y la formación de neointima mejorando la actividad de Nur77.
- La activación del receptor nuclear Nur77 representa una estrategia terapéutica prometedora para el tratamiento de la restenosis por stent.
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