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El exceso de O-GlcNAcilación causa insuficiencia cardíaca y muerte súbita
Priya Umapathi1,2, Olurotimi O Mesubi1,2, Partha S Banerjee3
1Division of Cardiology (P.U., O.O.M., N.A., Q.W., E.D.L., Y.W., J.M.G., O.E.R.G., M.E.A.), The Johns Hopkins University School of Medicine, Baltimore, MD.
Circulation
|February 17, 2021
Resumen
El exceso de O-GlcNAcilación causa insuficiencia cardíaca por deterioro de la energía mitocondrial. La atenuación de la O-GlcNAcilación es beneficiosa contra la remodelación cardíaca y puede ofrecer una nueva estrategia terapéutica para la cardiomiopatía.
Área de la Ciencia:
- La bioquímica
- Biología cardiovascular
- Regulación del metabolismo
Sus antecedentes:
- La insuficiencia cardíaca es un problema de salud mundial importante, relacionado con la obesidad, la hipertensión y la diabetes.
- La O-GlcNAcilación, una modificación posttranslacional, actúa como un sensor metabólico para el estrés celular.
- Se observa una elevación de la O-GlcNAcilación en la insuficiencia cardíaca, pero su papel causal en la miocardiopatía no está claro.
Objetivo del estudio:
- Investigar el impacto directo de la O-GlcNAcilación en la función y la patología cardíacas.
- Determinar si la modulación de la O-GlcNAc transferasa (OGT) u O-GlcNAc-asa (OGA) afecta la salud del corazón.
Principales métodos:
- Desarrollo de modelos de ratones transgénicos con sobreexpresión específica cardíaca de OGT y OGA.
- Evaluación de la función cardíaca, las arritmias y la supervivencia en respuesta a los niveles alterados de O-GlcNAcilación.
- Análisis de la energía mitocondrial, específicamente la actividad del Complejo I, y la remodelación patológica bajo estrés.
Principales resultados:
- La sobreexpresión de la OGT miocárdica condujo a un aumento de la O-GlcNAcilación, miocardiopatía dilatada, arritmias y muerte prematura.
- La sobreexpresión de OGA redujo la O-GlcNAcilación, mantuvo la función cardíaca normal y confirió resistencia a la insuficiencia cardíaca inducida por sobrecarga de presión.
- El cruce de modelos OGT y OGA rescató la cardiomiopatía y mejoró la actividad del Complejo I mitocondrial, implicando energías en la patología mediada por O-GlcNAc.
Conclusiones:
- La excesiva O-GlcNAcilación causa directamente la cardiomiopatía, en parte debido a la energía mitocondrial deteriorada.
- La actividad OGA mejorada es bien tolerada y la atenuación de la O-GlcNAcilación protege contra la remodelación cardíaca patológica.
- La modulación de O-GlcNAcilación presenta una nueva vía terapéutica potencial para el tratamiento de la cardiomiopatía y la insuficiencia cardíaca.
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