Nucleoside Diphosphate Kinase-C Suppresses cAMP Formation in Human Heart Failure
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Nucleoside Diphosphate Kinase-C Suppresses cAMP Formation in Human Heart Failure. / Abu-Taha, Issam H; Heijman, Jordi; Hippe, Hans-Jörg; Wolf, Nadine M; El-Armouche, Ali; Nikolaev, Viacheslav O; Schäfer, Marina; Würtz, Christina; Neef, Stefan; Voigt, Niels; Baczkó, István; Varró, András; Müller, Marion; Meder, Benjamin; Katus, Hugo A; Spiger, Katharina; Vettel, Christiane; Lehmann, Lorenz H; Backs, Johannes; Skolnik, Edward Y; Lutz, Susanne; Dobrev, Dobromir; Wieland, Thomas.
In: CIRCULATION, Vol. 135, No. 9, 28.02.2017, p. 881-897.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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TY - JOUR
T1 - Nucleoside Diphosphate Kinase-C Suppresses cAMP Formation in Human Heart Failure
AU - Abu-Taha, Issam H
AU - Heijman, Jordi
AU - Hippe, Hans-Jörg
AU - Wolf, Nadine M
AU - El-Armouche, Ali
AU - Nikolaev, Viacheslav O
AU - Schäfer, Marina
AU - Würtz, Christina
AU - Neef, Stefan
AU - Voigt, Niels
AU - Baczkó, István
AU - Varró, András
AU - Müller, Marion
AU - Meder, Benjamin
AU - Katus, Hugo A
AU - Spiger, Katharina
AU - Vettel, Christiane
AU - Lehmann, Lorenz H
AU - Backs, Johannes
AU - Skolnik, Edward Y
AU - Lutz, Susanne
AU - Dobrev, Dobromir
AU - Wieland, Thomas
PY - 2017/2/28
Y1 - 2017/2/28
N2 - 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 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 Gαi2 was increased, whereas 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 with 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.
AB - 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 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 Gαi2 was increased, whereas 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 with 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.
U2 - 10.1161/CIRCULATIONAHA.116.022852
DO - 10.1161/CIRCULATIONAHA.116.022852
M3 - SCORING: Journal article
C2 - 27927712
VL - 135
SP - 881
EP - 897
JO - CIRCULATION
JF - CIRCULATION
SN - 0009-7322
IS - 9
ER -