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La cascada Integrin-YAP/TAZ-JNK media el efecto ateroprotector del flujo de corte unidireccional
Li Wang1,2, Jiang-Yun Luo1,2, Bochuan Li3,4
1Institute of Vascular Medicine, Shenzhen Research Institute and Li Ka Shing Institute of Health Sciences, Chinese University of Hong Kong, Hong Kong, China.
Nature
|December 8, 2016
Resumen
La actividad endotelial de YAP/TAZ está regulada por el flujo sanguíneo, con inhibición que reduce la inflamación y la aterosclerosis. Dirigirse a la vía integrina-Gα13-RhoA-YAP ofrece una nueva estrategia terapéutica para la aterosclerosis.
Área de la Ciencia:
- Biología cardiovascular
- Mecanismos moleculares de las enfermedades
- Mecanobiología
Sus antecedentes:
- Los efectores de la vía Hippo YAP (proteína asociada al sí) y TAZ (coactivador transcripcional con motivo de unión a PDZ) median estímulos mecánicos.
- El papel de YAP/TAZ en la mecanotransducción inducida por el flujo sanguíneo y la patogénesis de la aterosclerosis no se comprende completamente.
Objetivo del estudio:
- Investigar la regulación de la actividad endotelial YAP/TAZ por los patrones de flujo sanguíneo.
- Determinar el papel de YAP/TAZ en el desarrollo de la aterosclerosis e identificar posibles objetivos terapéuticos.
Principales métodos:
- Actividad endotelial YAP/TAZ estudiada bajo diferentes condiciones de esfuerzo de corte.
- Se utilizaron modelos in vivo (ApoE-/- ratones) con sobreexpresión YAP específica del endotelio y knockdown Yap (CRISPR/Cas9).
- Se examinaron los efectos de los agentes antiateroscleróticos existentes y la activación de la integrina en la formación de placas.
Principales resultados:
- El flujo perturbado de ateroprono aumenta la actividad de YAP/TAZ, mientras que la tensión de corte unidireccional ateroprotectora la inhibe.
- La tensión de corte unidireccional activa la integrina, inhibiendo la RhoA y suprimiendo la YAP/TAZ.
- La inhibición de YAP/TAZ reduce la inflamación, la infiltración de monocitos y retrasa el desarrollo de la aterosclerosis in vivo.
- Las estatinas inhiben la YAP/TAZ, y dirigirse a la vía integrina-Gα13-RhoA-YAP reduce la formación de placa.
Conclusiones:
- La actividad endotelial YAP / TAZ está regulada diferencialmente por los patrones de flujo sanguíneo, lo que afecta a la aterosclerosis.
- La vía de señalización integrina-Gα13-RhoA-YAP es un mediador crítico de la mecanotransducción inducida por la hemodinámica en la aterosclerosis.
- La inhibición de esta vía presenta una nueva estrategia terapéutica prometedora para el tratamiento de la aterosclerosis.
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