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La fosforilación de la proteína C de unión a la miosina cardíaca en un fondo de cadena pesada {beta}-miosina
Sakthivel Sadayappan1, James Gulick, Raisa Klevitsky
1Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Ohio, USA.
Circulation
|February 25, 2009
Resumen
La fosforilación de la proteína C de unión a la miosina cardíaca (cMyBP-C) es esencial para la función cardíaca normal en un entorno de cadena pesada de beta-miosina (beta-MyHC). Esta fosforilación también protege el corazón de la lesión por isquemia/reperfusión, lo que sugiere un potencial terapéutico.
Área de la Ciencia:
- Biología Cardiovascular Biología Cardiovascular
- Cardiología Molecular Cardiología Molecular
- Fisiología del músculo cardíaco Fisiología del músculo cardíaco
Sus antecedentes:
- La fosforilación de la proteína-C de unión a la miosina cardíaca (cMyBP-C) es un regulador clave de la contractilidad cardíaca.
- Estudios previos en corazones de cadena pesada de alfa-miosina (alfa-MyHC) mostraron que los fosfomiméticos cMyBP-C rescataron la disfunción cardíaca.
- La relevancia para los corazones humanos, que expresan predominantemente beta-miosina de cadena pesada (beta-MyHC), no estaba clara.
Objetivo del estudio:
- Para investigar el papel de la fosforilación cMyBP-C en un fondo beta-MyHC.
- Para determinar si la fosforilación cMyBP-C es esencial para la función cardíaca en los corazones beta-MyHC.
- Evaluar los efectos cardioprotectores de la fosforilación cMyBP-C contra la lesión por isquemia/reperfusión en un contexto beta-MyHC.
Principales métodos:
- Se generaron ratones transgénicos que expresaban diferentes formas de cMyBP-C (WT, no fosforilable, fosfomimético) en un fondo beta-MyHC.
- Cruzó estos ratones en un fondo cMyBP-C-nulo para eliminar el cMyBP-C. endógeno.
- Evaluación de la función cardíaca, la supervivencia y la respuesta a la lesión por isquemia/reperfusión.
Principales resultados:
- Los ratones que carecían de fosforilación cMyBP-C funcional en el fondo beta-MyHC (cMyBP-C(AllP) ((-): ((t/t) /beta) exhibieron muerte prematura debido a insuficiencia cardíaca.
- Los corazones que expresan cMyBP-C de tipo fosfomimético o salvaje en el fondo beta-MyHC no mostraron morbilidad o mortalidad significativas.
- El cMyBP-C fosfomimético protegió significativamente estos corazones de las lesiones por isquemia/reperfusión.
Conclusiones:
- cLa fosforilación de MyBP-C es crítica para mantener la función basal del miocardio en el entorno beta-MyHC.
- cLa fosforilación MyBP-C confiere una protección significativa contra la lesión por isquemia/reperfusión en el trasfondo beta-MyHC relevante para el ser humano.
- Dirigirse a la fosforilación cMyBP-C representa una estrategia terapéutica prometedora para las afecciones cardíacas humanas.
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