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

• DOI: 10.1161/circulationaha.116.022852
• Publication Date: 2016-12-08T02:50:19Z
• Authors: Issam H. Abu-Taha; Jordi Heijman; Hans-Jörg Hippe; Nadine M. Wolf; Ali El-Armouche; Viacheslav O. Nik...; 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
• Keywords: Isoprenaline; Contractility

Background: Chronic heart failure (HF) is associated with altered signal transduction via β-adrenoceptors and G proteins reduced cAMP formation. Nucleoside diphosphate kinases (NDPKs) are enriched at the plasma membrane of patients end-stage HF, but functional consequences this largely unknown, particularly for NDPK-C. Here, we investigated potential role NDPK-C in cardiac formation contractility. Methods: Real-time polymerase chain reaction, (far) Western blot, immunoprecipitation, immunocytochemistry were used to study expression, interaction proteins, localization NDPKs. levels determined immunoassays or fluorescent resonance energy transfer, contractility was cardiomyocytes (cell shortening) vivo (fractional shortening). Results: essential an NDPK-B/G protein complex. Protein mRNA upregulated human rats after long-term isoprenaline stimulation through osmotic minipumps, incubation rat neonatal isoprenaline. Isoprenaline also promoted translocation membrane. Overexpression increased sensitized isoprenaline-induced augmentation contractility, whereas knockdown decreased levels. In vivo, depletion zebrafish embryos caused edema ventricular dysfunction. NDPK-B knockout mice had unaltered expression showed contractile dysfunction exacerbated remodeling during stimulation. complex between Gα i2 NDPK-C/Gα s decreased, producing a switch that may contribute NDPK-C–dependent reduction HF. Conclusions: Our findings identify as requirement both NDPK isoforms proteins. novel critical regulator β-adrenoceptor/cAMP signaling By switching from activation, lower related