Nucleoside Diphosphate Kinase-C Suppresses cAMP Formation in Human Heart Failure.

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Circulation. 2017 Feb 28;135(9):881-897. doi: 10.1161/CIRCULATIONAHA.116.022852. Epub 2016 Dec 07.

Nucleoside Diphosphate Kinase-C Suppresses cAMP Formation in Human Heart Failure.

Circulation

Issam H Abu-Taha, Jordi Heijman, Hans-Jörg Hippe, Nadine M Wolf, Ali El-Armouche, Viacheslav O Nikolaev, Marina Schäfer, Christina M Würtz, Stefan Neef, Niels Voigt, István Baczkó, András Varró, Marion Müller, Benjamin Meder, Hugo A Katus, Katharina Spiger, Christiane Vettel, Lorenz H Lehmann, Johannes Backs, Edward Y Skolnik, Susanne Lutz, Dobromir Dobrev, Thomas Wieland

Affiliations

From 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.
From 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. [email protected] [email protected].

PMID: 27927712 DOI: 10.1161/CIRCULATIONAHA.116.022852

Abstract

BACKGROUND: Chronic heart failure (HF) is associated with altered signal transduction via β-adrenoceptors and G proteins and with reduced cAMP formation. Nucleoside diphosphate kinases (NDPKs) are enriched at the plasma membrane of patients with end-stage HF, but the functional consequences of this are largely unknown, particularly for NDPK-C. Here, we investigated the potential role of NDPK-C in cardiac cAMP formation and contractility.

METHODS: Real-time polymerase chain reaction, (far) Western blot, immunoprecipitation, and immunocytochemistry were used to study the expression, interaction with G proteins, and localization of NDPKs. cAMP levels were determined with immunoassays or fluorescent resonance energy transfer, and contractility was determined in cardiomyocytes (cell shortening) and in vivo (fractional shortening).

RESULTS: NDPK-C was essential for the formation of an NDPK-B/G protein complex. Protein and mRNA levels of NDPK-C were upregulated in end-stage human HF, in rats after long-term isoprenaline stimulation through osmotic minipumps, and after incubation of rat neonatal cardiomyocytes with isoprenaline. Isoprenaline also promoted translocation of NDPK-C to the plasma membrane. Overexpression of NDPK-C in cardiomyocytes increased cAMP levels and sensitized cardiomyocytes to isoprenaline-induced augmentation of contractility, whereas NDPK-C knockdown decreased cAMP levels. In vivo, depletion of NDPK-C in zebrafish embryos caused cardiac edema and ventricular dysfunction. NDPK-B knockout mice had unaltered NDPK-C expression but showed contractile dysfunction and exacerbated cardiac remodeling during long-term isoprenaline stimulation. In human end-stage HF, the complex formation between NDPK-C and Gα

CONCLUSIONS: Our findings identify NDPK-C as an essential requirement for both the interaction between NDPK isoforms and between NDPK isoforms and G proteins. NDPK-C is a novel critical regulator of β-adrenoceptor/cAMP signaling and cardiac contractility. By switching from Gα

Keywords: heart failure; myocardial contraction; receptors, adrenergic, beta; signal transduction

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