PUBLICATION

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

Authors
Abu-Taha, I.H., Heijman, J., Hippe, H.J., Wolf, N.M., El-Armouche, A., Nikolaev, V.O., Schäfer, M., Würtz, C., Neef, S., Voigt, N., Baczkó, I., Varró, A., Müller, M., Meder, B., Katus, H.A., Spiger, K., Vettel, C., Lehmann, L.H., Backs, J., Skolnik, E.Y., Lutz, S., Dobrev, D., Wieland, T.
ID
ZDB-PUB-161209-4
Date
2017
Source
Circulation   135(9): 881-897 (Journal)
Registered Authors
Meder, Benjamin, Wolf, Nadine
Keywords
NDPK, contractility, heart failure, receptors, adrenergic, beta, signal transduction
MeSH Terms
  • Animals
  • Cell Line
  • Cell Membrane/metabolism
  • Cyclic AMP/analysis*
  • Cyclic AMP/metabolism
  • Disease Models, Animal
  • Embryo, Nonmammalian/metabolism
  • GTP-Binding Protein alpha Subunits, G12-G13/metabolism
  • Heart Failure/metabolism
  • Heart Failure/pathology*
  • Humans
  • Isoproterenol/pharmacology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Myocytes, Cardiac/cytology
  • Myocytes, Cardiac/drug effects
  • Myocytes, Cardiac/metabolism
  • NM23 Nucleoside Diphosphate Kinases/analysis*
  • NM23 Nucleoside Diphosphate Kinases/antagonists & inhibitors
  • NM23 Nucleoside Diphosphate Kinases/genetics
  • NM23 Nucleoside Diphosphate Kinases/metabolism
  • Protein Binding
  • Protein Isoforms/chemistry
  • Protein Isoforms/genetics
  • Protein Isoforms/metabolism
  • RNA Interference
  • RNA, Small Interfering/metabolism
  • Rats
  • Rats, Wistar
  • Zebrafish/growth & development
PubMed
27927712 Full text @ Circulation
Abstract
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.
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).
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 Gαi2 was increased whereas the NDPK-C/Gαs interaction was decreased, producing a switch that may contribute to an NDPK-C-dependent cAMP reduction in HF.
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 Gαs to Gαi2 activation, NDPK-C may contribute to lower cAMP levels and the related contractile dysfunction in HF.
Genes / Markers
Figures
Show all Figures
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Antibodies
Orthology
Engineered Foreign Genes
Mapping