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

2017 | journal article. A publication with affiliation to the University of Göttingen.

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​Nucleoside Diphosphate Kinase-C Suppresses cAMP Formation in Human Heart Failure​
Abu-Taha, I. H.; Heijman, J.; Hippe, H.-J.; Wolf, N. M.; El-Armouche, A. ; Nikolaev, V. O.   & Schäfer, M.  et al.​ (2017) 
Circulation135(9) pp. 881​-897​.​ DOI: https://doi.org/10.1161/CIRCULATIONAHA.116.022852 

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Authors
Abu-Taha, Issam H.; Heijman, Jordi; Hippe, Hans-Jörg; Wolf, Nadine M.; El-Armouche, Ali ; Nikolaev, Viacheslav O. ; Schäfer, Marina ; Würtz, Christina M. ; Neef, Stefan; Voigt, Niels ; Baczkó, István; Varró, András; Müller, Marion ; Meder, Benjamin; Katus, Hugo A.; Spiger, Katharina; Vettel, Christiane ; Lehmann, Lorenz H.; Backs, Johannes; Skolnik, Edward Y.; Lutz, Susanne ; Dobrev, Dobromir; Wieland, Thomas
Abstract
Background: Chronic heart failure (HF) is associated with altered signal transduction via -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 G(i2) was increased whereas the NDPK-C/G(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 -adrenoceptor/cAMP signaling and cardiac contractility. By switching from G(s) to G(i2) activation, NDPK-C may contribute to lower cAMP levels and the related contractile dysfunction in HF.
Issue Date
2017
Status
published
Publisher
Lippincott Williams & Wilkins
Journal
Circulation 
ISSN
0009-7322
eISSN
1524-4539
ISSN
1524-4539; 0009-7322
Language
English

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