Medizinische Universität Graz Austria/Österreich - Forschungsportal - Medical University of Graz
Gewählte Publikation:
SHR Neuro Krebs Kardio Lipid Stoffw Microb
Abu-Taha, IH; Heijman, J; Hippe, HJ; Wolf, NM; El-Armouche, A; Nikolaev, VO; Schäfer, M; Würtz, CM; Neef, S; Voigt, N; Baczkó, I; Varró, A; Müller, M; Meder, B; Katus, HA; Spiger, K; Vettel, C; Lehmann, LH; Backs, J; Skolnik, EY; Lutz, S; Dobrev, D; Wieland, T.
Nucleoside Diphosphate Kinase-C Suppresses cAMP Formation in Human Heart Failure
CIRCULATION. 2017; 135(9): 881-897.
Doi: 10.1161/CIRCULATIONAHA.116.022852
Web of Science
PubMed
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- Co-Autor*innen der Med Uni Graz
- Heijman Jordi
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- 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.
- Find related publications in this database (Keywords)
- heart failure
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