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El circuito de retroalimentación molecular del receptor cannabinoide 2-centric impulsa la necroptosis en las lesiones
Pan Gao1, Mengying Cao1, Xueli Jiang1
1Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital and Institutes of Biomedical Sciences, Fudan University, China (P.G., M.C., X.J., X.W., G.Z., C.Y., J.G., Y.Z.).
Circulation
|November 30, 2022
Resumen
La necroptosis, una forma de muerte celular programada, conduce a la disfunción cardíaca diabética después de la apoptosis. Dirigirse al receptor cannabinoide 2 (CB2R) ofrece una estrategia terapéutica prometedora para esta afección.
Área de la Ciencia:
- Biología cardiovascular
- Investigación de las enfermedades metabólicas
- Mecanismos de muerte celular
Sus antecedentes:
- La disfunción cardíaca diabética es una complicación significativa de la diabetes, impulsada principalmente por la muerte celular.
- El momento preciso y la secuencia de las vías de muerte celular en los corazones diabéticos siguen siendo poco conocidos.
- La identificación de tipos específicos de muerte celular y puntos de intervención terapéutica es crucial para el tratamiento de la cardiomiopatía diabética.
Objetivo del estudio:
- Para identificar el camino específico de muerte celular responsable de la disfunción cardíaca diabética.
- Para aclarar los mecanismos moleculares que regulan esta vía de muerte celular.
- Proponer una nueva estrategia terapéutica dirigida a esta vía para la enfermedad cardíaca diabética.
Principales métodos:
- Se utilizaron modelos de ratón con diabetes tipo 1 y tipo 2 (db/db, HFD/STZ, inducida por STZ).
- Se evaluó la apoptosis y la necroptosis en corazones de ratones diabéticos en diferentes edades.
- Empleó bibliotecas de fármacos de receptores acoplados a proteínas G, modulación farmacológica / genética, líneas celulares estables y anticuerpos de fosforilación personalizados para estudios mecanicistas.
Principales resultados:
- La necroptosis se activó después de la apoptosis en etapas posteriores de la diabetes y causó directamente la disfunción cardíaca.
- El receptor cannabinoide 2 (CB2R) fue identificado como un regulador clave de la necroptosis.
- La CB2R normalmente reprime la necroptosis a través de BACH2; la glucosa alta interrumpe esto al promover la internalización de CB2R y la posterior fosforilación y degradación de CB2R mediadas por MLKL, creando un bucle de retroalimentación.
Conclusiones:
- Un nuevo bucle regulador molecular que involucra CB2R y BACH2 controla la necróptosis en el corazón diabético.
- La activación de CB2R reprime la necroptosis, mientras que la activación de MLKL conduce a la fosforilación y degradación de CB2R, formando un mecanismo de retroalimentación negativa.
- Dirigirse a la vía de necroptosis centrada en CB2R presenta una estrategia terapéutica prometedora para la disfunción cardíaca diabética.
Palabras clave:
Proteína BACH2 humanaReceptor cannabinoide 2 y sus derivadoscardiomiopatías diabéticasLa necroptosisMás Videos Relacionados
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