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

Abu-Taha, I. H. and Heijman, J. and Hippe, H. J. and Wolf, N. M. and El-Armouche, A. and Baczkó, István and Varró, András (2017) Nucleoside Diphosphate Kinase-C Suppresses cAMP Formation in Human Heart Failure. CIRCULATION, 135 (9). pp. 881-897. ISSN 0009-7322

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Abstract

BACKGROUND: -Chronic heart failure (HF) is associated with altered signal transduction via beta-adrenoceptors and G proteins, and with reduced cAMP formation. Nucleoside diphosphate kinases (NDPKs) are enriched at the plasma membrane of end-stage HF patients, 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 PCR, (Far) Western blot, immunoprecipitation, and immunocytochemistry were used to study the expression, interaction with G proteins, and localization of NDPKs. cAMP levels were determined using 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 a NDPK-B/G proteins complex. Protein and mRNA levels of NDPK-C were up-regulated in end-stage human HF, in rats following chronic isoprenaline (ISO) stimulation through osmotic minipumps, and after incubation of rat neonatal cardiomyocytes with ISO. ISO also promoted translocation of NDPK-C to the plasma membrane. Overexpression of NDPK-C in cardiomyocytes increased cAMP levels and sensitized cardiomyocytes to ISO-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 chronic ISO stimulation. In human end-stage HF, the complex formation between NDPK-C and Galphai2 was increased, whereas NDPK-C/Galphas 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 with G proteins. NDPK-C is a novel critical regulator of beta-adrenoceptor/cAMP signaling and cardiac contractility. By switching from Galphas to Galphai2 activation, NDPK-C may contribute to lower cAMP levels and the related contractile dysfunction in HF.

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