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
-
- Protein Isoforms/chemistry
- Protein Isoforms/genetics
- Protein Isoforms/metabolism
- Animals
- Rats
- Disease Models, Animal
- Isoproterenol/pharmacology
- NM23 Nucleoside Diphosphate Kinases/analysis*
- NM23 Nucleoside Diphosphate Kinases/antagonists & inhibitors
- NM23 Nucleoside Diphosphate Kinases/genetics
- NM23 Nucleoside Diphosphate Kinases/metabolism
- Cyclic AMP/analysis*
- Cyclic AMP/metabolism
- Male
- Mice, Knockout
- Cell Line
- RNA Interference
- Cell Membrane/metabolism
- Humans
- Rats, Wistar
- GTP-Binding Protein alpha Subunits, G12-G13/metabolism
- Heart Failure/metabolism
- Heart Failure/pathology*
- RNA, Small Interfering/metabolism
- Protein Binding
- Myocytes, Cardiac/cytology
- Myocytes, Cardiac/drug effects
- Myocytes, Cardiac/metabolism
- Mice
- Mice, Inbred C57BL
- Embryo, Nonmammalian/metabolism
- Zebrafish/growth & development
- PubMed
- 27927712 Full text @ Circulation
Citation
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. (2017) Nucleoside Diphosphate Kinase-C Suppresses cAMP Formation in Human Heart Failure. Circulation. 135(9):881-897.
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 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.
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 Gαs to Gαi2 activation, NDPK-C may contribute to lower cAMP levels and the related contractile dysfunction in HF.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping