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Papel de la señalización del daño en el ADN en la hipertensión arterial pulmonar

Jolyane Meloche¹, Aude Pflieger, Mylène Vaillancourt

¹Department of Medicine, Laval University, Pulmonary Hypertension Research Group, IUCPQ Research Centre, Québec, Canada (J.M., A.P., M.V., F.P., C.G., A.C., S.B.-B., E.T., C.C., S.P., S.B.); and Vascular Biology Research Group, Department of Medicine, University of Alberta, Edmonton, Canada (R.P., S.Z., E.D.M.).

|November 26, 2013

Resumen

La hipertensión arterial pulmonar (HAP) implica daño en el ADN y inflamación. La orientación a la poli (ADP-ribosa) polimerasa-1 (PARP-1) se muestra prometedora para revertir la HAP, ofreciendo una nueva estrategia terapéutica.

Área de la Ciencia:

Biología Cardiovascular Biología Cardiovascular
La medicina molecular es una medicina molecular.
La señalización celular.

Sus antecedentes:

La hipertensión arterial pulmonar (HAP) está relacionada con la inflamación crónica y el daño al ADN.
Las células del músculo liso PAH (PASMCs) muestran un fenotipo pro-proliferativo y anti-apoptótico.
Este fenotipo es sostenido por la activación de miR-204, NFAT y HIF-1α.

Objetivo del estudio:

Para investigar el papel de la poli (ADP-ribosa) polimerasa-1 (PARP-1) en las HAP.
Para determinar si la activación de PARP-1 contribuye al fenotipo pro-proliferativo de las HAP-PASMCs.
Evaluar el potencial terapéutico de la inhibición de PARP-1 en la HAP.

Principales métodos:

Se evaluaron los marcadores de daño del ADN (53BP1, γ-H2AX) y la expresión/actividad de PARP-1 en tejidos y células humanas de HAP.
Investigó el efecto del factor de necrosis tumoral-α en PASMCs sanos.
Se analizó la regulación de miR-204, NFAT y HIF-1α por PARP-1.
Se midió la proliferación y la apoptosis PASMC.
Se probó un inhibidor de PARP (ABT-888) en modelos experimentales de ratas de HAP.

Principales resultados:

Los tejidos y células de HAP muestran un aumento del daño al ADN y la activación de PARP-1.
La inflamación induce el daño del ADN y la activación de PARP-1 en las PASMC.
La activación de PARP-1 desregula miR-204, activando NFAT y HIF-1α, promoviendo la proliferación y inhibiendo la apoptosis.
La inhibición de PARP-1 revirtió las HAP en modelos de ratas.

Conclusiones:

La vía de daño del ADN/PARP-1 es crucial para el desarrollo de la HAP.
PARP-1 es un nuevo objetivo terapéutico para la HAP.
La inhibición de la PARP-1 demuestra un potencial traslacional significativo para el tratamiento de la HAP.

Palabras clave:

Daños en el ADN daños en el ADN.Proteína PARP1, en el ser humano.Los microARN se encuentran en las microARN.hipertensión arterial pulmonar hipertensión arterial pulmonar

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