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Requisito para la actividad de la proteína quinasa activada por mitógeno p38 en la formación de neointima después de
Brandon M Proctor1, Xiaohua Jin, Traian S Lupu
1Center for Cardiovascular Research, Department of Medicine, Washington University, St. Louis, School of Medicine, ST. Louis, Mo., USA.
Circulation
|July 23, 2008
Resumen
La activación de las células musculares lisas vasculares p38alpha MAPK es crucial para la formación de lesiones neointimales después de la angioplastia. La inhibición de esta vía previene el desarrollo de la lesión y reduce la proliferación celular asociada y la replicación del ADN.
Área de la Ciencia:
- Biología Cardiovascular Biología Cardiovascular
- La medicina molecular es una medicina molecular.
- Biología celular vascular Biología celular vascular
Sus antecedentes:
- La angioplastia y la colocación de stents pueden conducir a la formación de lesiones neoinimales, una complicación de la enfermedad vascular aterosclerótica.
- La proteína 2 ligada al receptor del factor de crecimiento (Grb2) es esencial para la formación de neointima y la activación de p38 MAPK en las células musculares lisas vasculares (SMC).
- El papel específico del SMC vascular p38alpha MAPK en el desarrollo neointimal requiere más investigación.
Objetivo del estudio:
- Examinar el papel del SMC vascular p38alpha MAPK en el desarrollo de lesiones neointimales.
- Para dilucidar los mecanismos moleculares por los cuales p38alpha MAPK contribuye a la formación de neointima.
Principales métodos:
- Ratos transgénicos compuestos generados con expresión específica de SMC inducible a la doxiciclina de p38alfa MAPK dominante negativo (DN-p38alpha).
- Se administró doxiciclina para inducir la expresión de DN-p38alfa y se evaluó la formación de neointima después de la lesión carotídea.
- Utilizó un sistema de cultivo de SMC in vitro para investigar los efectos de la inhibición de p38alpha MAPK (SB202190 o siRNA) en la proliferación de SMC y los eventos moleculares relacionados.
Principales resultados:
- El tratamiento con doxiciclina indujo con éxito la expresión de DN-p38alpha en las arterias transgénicas de ratones.
- Los ratones tratados con doxiciclina mostraron resistencia a la formación de neointima y una activación reducida de la p38 MAPK después de una lesión carotídea.
- La inhibición de p38alpha MAPK en SMC cultivadas bloqueó la proliferación inducida por el factor de crecimiento derivado de plaquetas, la replicación del ADN, la fosforilación de la proteína del retinoblastoma y la inducción de la proteína 6 de mantenimiento del minicromosoma.
Conclusiones:
- La activación vascular del SMC p38alpha MAPK es un componente necesario para la formación de lesiones neointimales.
- p38alpha MAPK probablemente promueve la formación de neointima al facilitar la fosforilación de la proteína del retinoblastoma y la expresión de la proteína 6 de mantenimiento del minicromosoma.
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