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La proteína quinasa II y la proteína quinasa A dependientes de Ca2+/calmodulina regulan diferencialmente el retículo
Thomas H Fischer1, Jonas Herting, Theodor Tirilomis
1Abteilung Kardiologie und Pneumologie/Herzzentrum, Georg August Universität Göttingen, Robert-Koch-Strasse 40, Göttingen, Germany.
Circulation
|July 24, 2013
Resumen
En la insuficiencia cardíaca, el aumento de la fuga de Ca2+ en el retículo sarcoplásmico está relacionado con la disfunción del receptor de ryanodina tipo 2 (RyR2). La inhibición de la proteína quinasa II (CaMKII) dependiente de Ca2+/calmodulina es prometedora para el tratamiento de las arritmias y la disfunción contráctil.
Área de la Ciencia:
- Biología Cardiovascular Biología Cardiovascular
- Cardiología Molecular Cardiología Molecular
- La bioquímica es la bioquímica.
Sus antecedentes:
- La fuga de Ca2+ del retículo sarcoplásmico (SR) a través de la disfunción del receptor de ryanodina tipo 2 (RyR2) es crítica en la insuficiencia cardíaca humana (HF).
- Los mecanismos de la desregulación progresiva de RyR2 desde la hipertrofia cardíaca hasta la hiperfibrillación cardíaca siguen siendo controvertidos.
Objetivo del estudio:
- Investigar las funciones de la proteína quinasa II (CaMKII) y la proteína quinasa A (PKA) en la fosforilación de RyR2 y la fuga de SR Ca2+ durante la transición de la hipertrofia cardíaca a la HF.
- Evaluar el potencial terapéutico de la inhibición de CaMKII y PKA en la HF.
Principales métodos:
- Análisis del tejido miocárdico de controles sanos, pacientes con hipertrofia compensada y pacientes con IC.
- Medición de los niveles de fosforilación de RyR2 y la fuga de SR Ca2+).
- Evaluación de los efectos de los inhibidores de CaMKII y PKA en el manejo de SR Ca2+.
Principales resultados:
- En la hipertrofia, tanto CaMKII como PKA fosforilaban RyR2, y sus inhibidores reducían la fuga de Ca2+ de SR.
- En HF, la fuga de SR Ca2+ casi se duplicó, asociada con un aumento de la fosforilación de RyR2 dependiente de CaMKII.
- La inhibición de CaMKII redujo la fuga de Ca2+ de SR en HF, mientras que la inhibición de PKA empeoró la carga de Ca2+ de SR y la función sistólica.
Conclusiones:
- En la hipertrofia, el CaMKII y el PKA regulan la fuga de RyR2 y SR Ca2+.
- La transición a la HF implica un aumento de la fuga diastólica de Ca2+ y un ciclo perturbado de Ca2+, vinculado a una elevada fosforilación de RyR2 dependiente de CaMKII.
- La inhibición de CaMKII representa una estrategia terapéutica potencial para las arritmias y la disfunción contráctil relacionadas con la IC.
Palabras clave:
La proteína quinasa dependiente de calcio calmodulina tipo 2 es una proteína quinasa dependiente de calcio calmodulina tipo 2.La insuficiencia cardíaca es insuficiencia cardíaca.La hipertrofia es una hipertrofia.Las proteína kinases son las proteínas kinases.el retículo sarcoplásmico.
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