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Regulación de la contractilidad miocárdica y el tamaño celular por distintas vías de señalización PI3K-PTEN
Michael A Crackower1, Gavin Y Oudit, Ivona Kozieradzki
1IMBA, Institute for Molecular Biotechnology of the Austrian Academy of Sciences, c/o Dr. Bohr Gasse 7, A-1030, Vienna, Austria.
Cell
|September 26, 2002
Resumen
La vía PTEN/PI3K afecta el tamaño y la función de las células cardíacas. La pérdida de PTEN causa hipertrofia y reducción de la contractilidad, con PI3Kgamma regulando la contractilidad a través de la señalización cAMP.
Área de la Ciencia:
- Biología Cardiovascular Biología Cardiovascular
- La señalización molecular.
- Fisiología Celular Fisiología celular
Sus antecedentes:
- La vía de señalización de la fosfatasa y el homólogo de la tensina (PTEN) y la fosfoinositida 3-cinasa (PI3K) es crucial para regular los procesos celulares.
- La desregulación de esta vía está implicada en varias enfermedades cardiovasculares.
Objetivo del estudio:
- Para investigar el papel in vivo de PTEN en la hipertrofia de los cardiomiocitos y la función cardíaca.
- Para aclarar las funciones específicas de las diferentes isoformas de PI3K en la mediación de los efectos de PTEN en el corazón.
Principales métodos:
- Se utilizaron modelos de ratón con knockout PTEN específico para cardiomiocitos.
- Generó y analizó ratones mutantes dobles para desacoplar genéticamente la hipertrofia y los defectos de contractilidad.
- Investigó la participación de las isoformas PI3K (PI3Kalpha y PI3Kgamma) y la señalización de la AMP cíclica (cAMP).
Principales resultados:
- La inactivación de PTEN específica de los cardiomiocitos condujo a la hipertrofia cardíaca y a una disminución significativa de la contractilidad cardíaca.
- Se descubrió que la hipertrofia cardíaca y los defectos de contractilidad son genéticamente separables.
- PI3Kalpha medió cambios en el tamaño de los cardiomiocitos, mientras que PI3Kgamma reguló negativamente la contractilidad cardíaca.
- La inhibición de la contractilidad cardíaca por PI3Kgamma se relacionó con la supresión de la producción de cAMP, y la hipercontractilidad podría restablecerse mediante el bloqueo de la función de cAMP.
Conclusiones:
- El PTEN juega un papel vital en la regulación de la hipertrofia de los cardiomiocitos y la señalización del receptor acoplado a proteínas G (GPCR) in vivo.
- La vía PTEN-PI3Kgamma se identifica como un modulador clave de la contractilidad del músculo cardíaco.
- Las isoformas específicas de PI3K tienen funciones distintas en la fisiología cardíaca, destacando objetivos terapéuticos para afecciones cardiovasculares.
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