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La metaloproteasa-1 de la matriz plaquetaria media la trombogénesis mediante la activación de PAR1 en el sitio de un
Vishal Trivedi1, Adrienne Boire, Boris Tchernychev
1Department of Medicine, Tufts University School of Medicine, Molecular Oncology Research Institute, Tufts Medical Center, 800 Washington Street, Boston, MA 02111, USA.
Cell
|April 22, 2009
Resumen
La metaloproteasa-1 de la matriz plaquetaria (MMP-1) activa el receptor activado por proteasa-1 (PAR1) en las plaquetas, promoviendo la agregación. El bloqueo de esta interacción MMP-1-PAR1 puede prevenir la trombosis arterial.
Área de la Ciencia:
- La bioquímica es la bioquímica.
- Biología celular Biología celular.
- Hematología Hematología.
Sus antecedentes:
- Las metaloproteasas matriciales (MMP) están involucradas en varios procesos fisiológicos y patológicos.
- Los MMPs fueron tradicionalmente vistos como enzimas que degradan la matriz, pero poseen funciones de señalización.
- Los MMP plaquetarios influyen en la hemostasis y la supervivencia, pero sus mecanismos no están claros.
Objetivo del estudio:
- Para investigar el papel de señalización de las plaquetas MMP-1 en la activación y función de las plaquetas.
- Para dilucidar la interacción entre MMP-1 y sus receptores en las plaquetas.
- Evaluar el potencial terapéutico de dirigirse al eje MMP-1-PAR1 en la trombosis.
Principales métodos:
- Investigó la activación de MMP-1 en las superficies de las plaquetas tras la exposición al colágeno.
- Se analizó la escisión MMP-1 del receptor activado por proteasa-1 (PAR1).
- Se evaluaron las vías de señalización aguas abajo, incluyendo Rho-GTP, cambio de forma celular y señalización MAPK.
- Se evaluó el efecto del bloqueo de MMP1-PAR1 en la trombogénesis in vitro e in vivo.
Principales resultados:
- MMP-1 en plaquetas activa PAR1 en la superficie de las plaquetas.
- MMP-1 divide PAR1 en un sitio único, activando las vías Rho-GTP, el cambio de forma celular y la señalización MAPK.
- La activación de MMP-1 por el colágeno fibrilar promueve la agregación plaquetaria a través de PAR1.
- La inhibición de la interacción MMP1-PAR1 redujo la trombogénesis bajo el flujo arterial y en modelos animales.
Conclusiones:
- Las plaquetas MMP-1 señalan directamente a través de PAR1, vinculando la activación de la metaloproteinasa de la matriz a la señalización de la proteína G en las plaquetas.
- La vía MMP1-PAR1 es crucial para la agregación plaquetaria y la trombogénesis.
- Dirigirse a la interacción MMP1-PAR1 presenta una estrategia potencial para prevenir la trombosis arterial.
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