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

Author:

Abu-Taha Issam H.1,Heijman Jordi1,Hippe Hans-Jörg1,Wolf Nadine M.1,El-Armouche Ali1,Nikolaev Viacheslav O.1,Schäfer Marina1,Würtz Christina M.1,Neef Stefan1,Voigt Niels1,Baczkó István1,Varró András1,Müller Marion1,Meder Benjamin1,Katus Hugo A.1,Spiger Katharina1,Vettel Christiane1,Lehmann Lorenz H.1,Backs Johannes1,Skolnik Edward Y.1,Lutz Susanne1,Dobrev Dobromir1,Wieland Thomas1

Affiliation:

1. 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...

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 i2 was increased whereas the NDPK-C/Gα s interaction was decreased, producing a switch that may contribute to an NDPK-C–dependent cAMP reduction in HF. 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 s to Gα i2 activation, NDPK-C may contribute to lower cAMP levels and the related contractile dysfunction in HF.

Publisher

Ovid Technologies (Wolters Kluwer Health)

Subject

Physiology (medical),Cardiology and Cardiovascular Medicine

Reference50 articles.

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