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Nucleoside Diphosphate Kinase-C suprime la formación de cAMP en la insuficiencia cardíaca humana

Issam H Abu-Taha¹, Jordi Heijman¹, Hans-Jörg Hippe¹

¹From Institute of Experimental and Clinical Pharmacology and Toxicology, Mannheim Medical Faculty (I.H.A.-T., N.M.W., K.S., C.V., S.L., T.W.), and Department of Internal Medicine III (H.-J.H., N.M.W., M.M., B.M., H.-A.K., L.H.L., J.B.), Heidelberg University, Heidelberg-Mannheim, Germany; Institute of Pharmacology, West German Heart and Vascular Center, University Duisburg-Essen, Essen, Germany (I.H.A.-T., J.H., M.S., N.V., D.D.); Institute of Pharmacology and Toxicology, University Medical Center Göttingen, Germany (A.E.-A., C.M.W., S.L.); Department of Pharmacology and Toxicology, Medical Faculty Carl Gustav Carus, Dresden University of Technology, Germany (A.E.-A.); Institute of Experimental Cardiovascular Research, University Medical Center Hamburg-Eppendorf, Germany (V.O.N.); Department of Internal Medicine II, University of Regensburg, Germany (S.N.); Department of Pharmacology and Pharmacotherapy, Faculty of Medicine, University of Szeged, Hungary (I.B., A.V.); Division of Nephrology, New York University Langone Medical Center, New York (E.Y.S.); and DZHK (German Center for Cardiovascular Research), Partner Site HD/MA, Heidelberg-Mannheim, Germany (B.M., H.A.K., C.V., J.B., T.W.). The current affiliation for H.-J.H. is the Department of Cardiology and Angiology, University Hospital Schleswig-Holstein, Kiel, Germany.

|December 9, 2016

Resumen

La nucleosida difosfato quinasa-C (NDPK-C) regula la contractilidad cardíaca mediante la modulación de la señalización de la proteína G. Este estudio revela que el NDPK-C

Área de la Ciencia:

Biología cardiovascular
Biología celular molecular
La bioquímica

Sus antecedentes:

La insuficiencia cardíaca crónica (IC) implica una alteración de la señalización de la proteína G y una reducción de la formación de AMPc.
Las nucleosidas difosfatokinasas (NDPK) se encuentran en niveles más altos en las membranas plasmáticas de los pacientes con HF, pero su papel no está claro.
La función específica de NDPK-C en la producción y la contractilidad cardíacas de la cAMP requiere investigación.

Objetivo del estudio:

Investigar el papel de la Nucleoside Diphosphate Kinase-C (NDPK-C) en la formación de adenosina monofosfato cíclico (cAMP) en el corazón.
Para determinar el impacto de NDPK-C en la contractilidad cardíaca en la insuficiencia cardíaca.
Para aclarar los mecanismos moleculares que vinculan NDPK-C a la señalización de la proteína G en el corazón.

Principales métodos:

Se estudió la expresión de NDPK, la interacción de la proteína G y la localización utilizando técnicas de biología molecular (PCR, Western blot, inmunoprecipitación, inmunocitoquímica).
Niveles de cAMP cuantificados mediante pruebas inmunológicas y transferencia de energía de resonancia de Förster (FRET).
Evaluación de la contractilidad cardíaca en cardiomiocitos aislados y en modelos in vivo.

Principales resultados:

La NDPK-C es crucial para la formación del complejo de proteínas NDPK-B/G y está regulada al alza en modelos de insuficiencia cardíaca.
La sobreexpresión de NDPK-C aumentó los niveles de cAMP y la contractilidad, mientras que el knockdown los redujo.
En la insuficiencia cardíaca, la NDPK-C cambia la activación de la proteína G de Gαs a Gαi2, disminuyendo la cAMP y deteriorando la contractilidad.

Conclusiones:

NDPK-C es esencial para las interacciones de la isoforma NDPK y la proteína G, actuando como un regulador clave de la contractilidad cardíaca.
El interruptor de NDPK-C en la activación de la proteína G contribuye a la reducción de los niveles de cAMP y la disfunción contráctil en la insuficiencia cardíaca.
NDPK-C representa un nuevo objetivo terapéutico para el manejo de anomalías de señalización relacionadas con la insuficiencia cardíaca.

Palabras clave:

insuficiencia cardíaca contracción del miocardio receptores adrenérgicos, beta Transducción de señales

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