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Una vía dependiente de la trombospondina para una respuesta de estrés ER protectora
Jeffrey M Lynch1, Marjorie Maillet, Davy Vanhoutte
1Department of Pediatrics, Cincinnati Children's Hospital, University of Cincinnati, OH 45247, USA.
Cell
|June 12, 2012
Resumen
Las proteínas de las trombospondinas (Thbs) protegen contra lesiones cardíacas al mejorar la respuesta al estrés del retículo endoplasmático (ER). Thbs4 promueve específicamente el estrés adaptativo de ER, aumentando la función de ER y protegiendo el corazón durante la enfermedad.
Área de la Ciencia:
- Biología Cardiovascular Biología Cardiovascular
- Respuesta Celular al Estrés Respuesta Celular al Estrés
- La medicina molecular es una medicina molecular.
Sus antecedentes:
- Las trombospondinas (Thbs) son proteínas reguladas hacia arriba en los sitios de daño y remodelación de los tejidos.
- La respuesta al estrés del retículo endoplasmático (ER) se activa durante la enfermedad, regulando la homeostasis de las proteínas.
- No se ha explorado un posible vínculo entre Thbs y el estrés ER en la adaptación a la enfermedad.
Objetivo del estudio:
- Para investigar el papel de las trombospondinas (Thbs) como efectores de la respuesta adaptativa al estrés ER.
- Determinar la función de Thbs4 en lesiones cardíacas y mala adaptación.
- Para aclarar el mecanismo por el cual Thbs influye en la función ER y la protección celular.
Principales métodos:
- Se utilizaron modelos de ratones transgénicos Thbs4 y Thbs4 knockout específicos para el corazón.
- Analizó los factores de respuesta al estrés adaptativos de ER y la morfología de ER.
- Investigó la interacción entre Thbs y el factor de transcripción activador 6α (Atf6α) in vivo e in vitro.
- Evaluación de la lesión cardíaca y los fenotipos de mala adaptación.
Principales resultados:
- Los ratones transgénicos Thbs4 mostraron protección contra lesiones del miocardio, mientras que los ratones Thbs4(-/-) fueron sensibilizados.
- La inducción de Thbs condujo a perfiles adaptativos de factores de estrés ER y a la expansión de ER.
- Thbs se unen al dominio luminal ER de Atf6α, promoviendo su translocación nuclear.
- Los ratones Thbs4(-/-) exhibieron una activación Atf6α embotada, y la protección mediada por Thbs4 dependía de Atf6α.
Conclusiones:
- Las trombospondinas (Thbs) funcionan intracelularmente como efectores residentes en el ER de una respuesta adaptativa al estrés del ER.
- Thbs4 juega un papel protector en la remodelación cardíaca mediante el aumento de la función ER a través de la regulación de Atf6α.
- Este mecanismo destaca Thbs como un objetivo terapéutico potencial para las enfermedades cardiovasculares que involucran estrés ER.
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