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DAPK2 Regula la fosforilación de PKM2 en la treonina 45 para facilitar la aterosclerosis inducida por el flujo
Shuai Guo1,2, Long Xu1, Yixin Chen3
1Department of Physiology, Guangdong Key Laboratory of Vascular Diseases, Guangdong Provincial Key Laboratory of Protein Modification and Degradation, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, China (S.G., L.X., Y. Zhao, Y. Zhang, R.Y., Y.X.).
Circulation
|January 30, 2026
Resumen
La proteína quinasa 2 asociada a la muerte (DAPK2) impulsa la aterosclerosis mediante la fosforilación de la piruvato quinasa M2 (PKM2), promoviendo la inflamación endotelial. La inhibición de esta interacción DAPK2-PKM2 ofrece una estrategia terapéutica potencial para la aterosclerosis.
Área de la Ciencia:
- Biología Cardiovascular Biología Cardiovascular
- Mecanismos moleculares de la aterosclerosis
- Biología celular endotelial Biología celular endotelial
Sus antecedentes:
- El flujo sanguíneo perturbado, caracterizado por estrés de cizallamiento oscilatorio (OSS), contribuye a la formación de placa aterosclerótica a través de vías incompletamente comprendidas.
- La activación de la célula endotelial (CE) es un evento crítico temprano en la aterogénesis, influenciado por las fuerzas hemodinámicas.
- El papel de la proteína quinasa 2 asociada a la muerte (DAPK2) en la activación de la EC inducida por la OSS y la aterosclerosis requiere aclaración.
Objetivo del estudio:
- Para investigar la participación de DAPK2 en la activación de las células endoteliales y la aterosclerosis en condiciones de flujo sanguíneo alterado.
- Identificar los mecanismos moleculares por los cuales DAPK2 influye en las respuestas endoteliales al estrés de cizallamiento oscilatorio.
- Explorar el potencial de dirigir la vía DAPK2 como una estrategia terapéutica para la aterosclerosis.
Principales métodos:
- Se utilizaron datos genómicos y transcriptómicos públicos (microarray, RNA-seq, scRNA-seq) para identificar los factores sensibles a la OSS.
- Se emplean ensayos de espectrometría de masas, inmunoprecipitación y ligadura de proximidad para identificar proteínas de unión a DAPK2 y sitios de fosforilación.
- Se generaron y analizaron células endoteliales específicas Dapk2-deficientes y Pkm2 ratones mutantes en modelos de aterosclerosis (ligación de la arteria carótida, dieta occidental).
Principales resultados:
- La expresión de DAPK2 es regulada por OSS en las arterias humanas y murinas, suprimida por KLF2.
- La deficiencia específica de la EC Dapk2 redujo la activación de la EC y la aterogénesis en ratones Apoe.
- DAPK2 directamente fosforila la piruvato quinasa M2 (PKM2) en la treonina 45, promoviendo la dimerización de PKM2, la translocación nuclear y la activación de los genes inflamatorios (VCAM-1, ICAM-1) a través de STAT1.1.
- La fosforilación de PKM2 en T45 y STAT1 en Y701 está elevada en el endotelio de la atheroprona.
- La sobreexpresión de un mutante de PKM2 refractario al fósforo (Pkm2T45A) mitigó la atherogénesis inducida por el flujo perturbado.
Conclusiones:
- La fosforilación mediada por DAPK2 de PKM2 en la treonina 45 es un mecanismo clave que vincula el flujo sanguíneo perturbado con las respuestas inflamatorias endoteliales.
- Este eje DAPK2-PKM2 representa una nueva vía en la patogénesis de la aterosclerosis.
- Dirigirse a la fosforilación de PKM2 impulsada por DAPK2 presenta una potencial vía terapéutica para el tratamiento de la aterosclerosis.
Palabras clave:
La aterosclerosis es la aterosclerosis.muerte asociada con la proteína quinasa 2 asociada con la muerte.el flujo perturbado del flujo.células endoteliales de las células endoteliales.La inflamación es la inflamación de la inflamación.La piruvato quinasa M2 también es piruvato quinasa.
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