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La respuesta proteica desplegada como mecanismo compensatorio y objetivo terapéutico potencial en la miocardiopatía
Dries A M Feyen1,2, Isaac Perea-Gil1,3, Renee G C Maas4
1Cardiovascular Institute, Stanford University, CA (D.A.M.F., I.P.-G., J.A.A., N.V., M.V., P.L.A., K.S., M.M., I.K.).
Circulation
|April 30, 2021
Resumen
La respuesta proteica desplegada (UPR) es protectora en la cardiomiopatía por fosfolambano R14del. La activación de la UPR puede ofrecer una nueva estrategia terapéutica para esta afección cardíaca.
Área de la Ciencia:
- Biología cardiovascular
- Cardiología molecular
- Biología de las células madre
Sus antecedentes:
- La mutación del fosfolambano (PLN) R14del causa miocardiopatía dilatada y arritmias.
- Los mecanismos precisos que subyacen a la cardiomiopatía PLN R14del siguen sin estar claros.
- Actualmente no existen terapias dirigidas para la miocardiopatía PLN R14del.
Objetivo del estudio:
- Investigar los mecanismos moleculares de la miocardiopatía PLN R14del mediante el uso de células madre pluripotentes inducidas en humanos (hiPSC-CM).
- Explorar posibles estrategias terapéuticas dirigidas a las vías de enfermedad identificadas.
Principales métodos:
- Se utilizó la secuenciación de ARN unicelular en hiPSC-CM para identificar los mecanismos de la enfermedad.
- Utilizó ensayos de contractilidad 2D y 3D para evaluar la función cardíaca.
- Se investigó el papel de la vía de respuesta de la proteína desplegada (UPR) y se probó un activador de la UPR (inductor de BiP X) como intervención terapéutica.
Principales resultados:
- PLN R14del hiPSC-CMs exhibió déficits contráctiles, recapitulando el fenotipo de la enfermedad.
- La secuenciación de ARN de una sola célula reveló la activación de la UPR en modelos PLN R14del y corazones de pacientes.
- El silenciamiento de la vía UPR empeoró la disfunción contráctil, mientras que el tratamiento con BiP inductor X mejoró los déficits de una manera dependiente de la dosis.
Conclusiones:
- La respuesta proteica desplegada (UPR) juega un papel protector en la cardiomiopatía PLN R14del.
- La modulación de la UPR presenta una vía terapéutica prometedora para el tratamiento de la enfermedad cardíaca asociada a PLN R14del.
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