Lutz, Susanne

[["dc.bibliographiccitation.firstpage","1261"],["dc.bibliographiccitation.issue","6"],["dc.bibliographiccitation.journal","Cellular Signalling"],["dc.bibliographiccitation.lastpage","1269"],["dc.bibliographiccitation.volume","24"],["dc.contributor.author","Carbajo-Lozoya, Javier"],["dc.contributor.author","Lutz, Susanne"],["dc.contributor.author","Feng, Yuxi"],["dc.contributor.author","Kroll, Jens"],["dc.contributor.author","Hammes, Hans-Peter"],["dc.contributor.author","Wieland, Thomas"],["dc.date.accessioned","2018-11-07T09:10:09Z"],["dc.date.available","2018-11-07T09:10:09Z"],["dc.date.issued","2012"],["dc.description.abstract","Vascular endothelial growth factor (VEGF) is a main stimulator of pathological vessel formation. Nevertheless, increasing evidence suggests that Angiotensin II (Ang II) can play an augmentory role in this process. We thus analyzed the contribution of the two Ang II receptor types, AT(1)R and AT(2)R, in a mouse model of VEGF-driven angiogenesis, i.e. oxygen-induced proliferative retinopathy. Application of the AT(1)R antagonist telmisartan but not the AT(2)R antagonist PD123,319 largely attenuated the pathological response. A direct effect of Ang II on endothelial cells (EC) was analyzed by assessing angiogenic responses in primary bovine retinal and immortalized rat microvascular EC. Selective stimulation of the AT(1)R by Ang II in the presence of PD123,319 revealed a pro-angiogenic activity which further increased VEGF-driven EC sprouting and migration. In contrast, selective stimulation of the AT(2)R by either CGP42112A or Ang II in the presence of telmisartan inhibited the VEGF-driven angiogenic response. Using specific inhibitors (pertussis toxin, RGS proteins, kinase inhibitors) we identified G(12/13) and G(i) dependent signaling pathways as the mediators of the AT(1)R-induced angiogenesis and the AT(2)R-induced inhibition, respectively. As AT(1)R and AT(2)R stimulation displays opposing effects on the activity of the monomeric GTPase RhoA and pro-angiogenic responses to Ang II and VEGF requires activation of Rho-dependent kinase (ROCK), we conclude that the opposing effects of the Ang II receptors on VEGF-driven angiogenesis converge on the regulation of activity of RhoA-ROCK-dependent EC migration. (c) 2012 Elsevier Inc. All rights reserved."],["dc.description.sponsorship","Deutsche Forschungsgemeinschaft"],["dc.identifier.doi","10.1016/j.cellsig.2012.02.005"],["dc.identifier.isi","000303097200017"],["dc.identifier.pmid","22374305"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/26425"],["dc.notes.status","zu prüfen"],["dc.notes.submitter","Najko"],["dc.publisher","Elsevier Science Inc"],["dc.relation.issn","0898-6568"],["dc.title","Angiotensin H modulates VEGF-driven angiogenesis by opposing effects of type 1 and type 2 receptor stimulation in the microvascular endothelium"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.peerReviewed","yes"],["dc.type.status","published"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.firstpage","165"],["dc.bibliographiccitation.issue","2"],["dc.bibliographiccitation.journal","Journal of Molecular and Cellular Cardiology"],["dc.bibliographiccitation.lastpage","175"],["dc.bibliographiccitation.volume","53"],["dc.contributor.author","Vettel, Christiane"],["dc.contributor.author","Wittig, Karola"],["dc.contributor.author","Vogt, Andreas"],["dc.contributor.author","Wuertz, Christina M."],["dc.contributor.author","El-Armouche, Ali"],["dc.contributor.author","Lutz, Susanne"],["dc.contributor.author","Wieland, Thomas"],["dc.date.accessioned","2018-11-07T09:07:59Z"],["dc.date.available","2018-11-07T09:07:59Z"],["dc.date.issued","2012"],["dc.description.abstract","Activation of alpha(1)-adrenoceptors (alpha(1)-AR) by high catecholamine levels, e.g. in heart failure, is thought to be a driving force of cardiac hypertrophy. In this context several downstream mediators and cascades have been identified to potentially play a role in cardiomyocyte hypertrophy. One of these proteins is the monomeric G protein Rac1. However, until now it is unclear how this essential G protein is activated by alpha(1)-AR agonists and what are the downstream targets inducing cellular growth. By using protein-based as well as pharmacological inhibitors and the shRNA technique, we demonstrate that in neonatal rat cardiomyocytes (NRCM) Rac1 is activated via a cascade involving the alpha(1A)-AR subtype, G(i)beta gamma, the phosphoinositide-3'-kinase and the guanine nucleotide exchange factor Tiam1. We further demonstrate that this signaling induces an increase in protein synthesis, cell size and atrial natriuretic peptide expression. We identified the p21-activated kinase 2 (PAK2) as a downstream effector of Rac1 and were able to link this cascade to the activation of the pro-hypertrophic kinases ERK1/2 and p90RSK. Our data thus reveal a prominent role of the alpha(1A)-AR/G(i)beta gamma/Tiam1-mediated activation of Rac1 and its effector PAK2 in the induction of hypertrophy in NRCM. (C) 2012 Elsevier Ltd. All rights reserved."],["dc.identifier.doi","10.1016/j.yjmcc.2012.04.015"],["dc.identifier.isi","000306451600003"],["dc.identifier.pmid","22564263"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/25922"],["dc.notes.status","zu prüfen"],["dc.notes.submitter","Najko"],["dc.publisher","Academic Press Ltd- Elsevier Science Ltd"],["dc.relation.issn","1095-8584"],["dc.relation.issn","0022-2828"],["dc.title","A novel player in cellular hypertrophy: G(i)beta gamma/PI3K-dependent activation of the RacGEF TIAM-1 is required for alpha(1)-adrenoceptor induced hypertrophy in neonatal rat cardiomyocytes"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.peerReviewed","yes"],["dc.type.status","published"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.firstpage","39"],["dc.bibliographiccitation.journal","Journal of Molecular and Cellular Cardiology"],["dc.bibliographiccitation.lastpage","54"],["dc.bibliographiccitation.volume","88"],["dc.contributor.author","Ongherth, Anita"],["dc.contributor.author","Pasch, Sebastian"],["dc.contributor.author","Wuertz, Christina M."],["dc.contributor.author","Nowak, Karolin"],["dc.contributor.author","Kittana, Naim"],["dc.contributor.author","Weis, Cleo A."],["dc.contributor.author","Jatho, Aline"],["dc.contributor.author","Vettel, Christiane"],["dc.contributor.author","Tiburcy, Malte"],["dc.contributor.author","Toischer, Karl"],["dc.contributor.author","Hasenfuß, Gerd"],["dc.contributor.author","Zimmermann, Wolfram-Hubertus"],["dc.contributor.author","Wieland, Thomas"],["dc.contributor.author","Lutz, Susanne"],["dc.date.accessioned","2017-09-07T11:43:27Z"],["dc.date.available","2017-09-07T11:43:27Z"],["dc.date.issued","2015"],["dc.description.abstract","Cardiac remodeling, a hallmark of heart disease, is associated with intense auto- and paracrine signaling leading to cardiac fibrosis. We hypothesized that the specific mediator of G(q/11)-dependent RhoA activation p63RhoGEF, which is expressed in cardiac fibroblasts, plays a role in the underlying processes. We could show that p63RhoGEF is up-regulated in mouse hearts subjected to transverse aortic constriction (TAC). In an engineered heart muscle model (EHM), p63RhoGEF expression in cardiac fibroblasts increased resting and twitch tensions, and the dominant negative p63 Delta N decreased both. In an engineered connective tissue model (ECT), p63RhoGEF increased tissue stiffness and its knockdown as well as p63 Delta N reduced stiffness. In 2D cultures of neonatal rat cardiac fibroblasts, p63RhoGEF regulated the angiotensin II (Ang II)-dependent RhoA activation, the activation of the serum response factor, and the expression and secretion of the connective tissue growth factor (CTGF). All these processes were inhibited by the knockdown of p63RhoGEF or by p63 Delta N likely based on their negative influence on the actin cytoskeleton. Moreover, we show that p63RhoGEF also regulates CTGF in engineered tissues and correlates with it in the TAC model. Finally, confocal studies revealed a closely related localization of p63RhoGEF and CTGF in the trans-Golgi network. (C) 2015 Published by Elsevier Ltd."],["dc.identifier.doi","10.1016/j.yjmcc.2015.09.009"],["dc.identifier.gro","3141795"],["dc.identifier.isi","000365059300004"],["dc.identifier.pmid","26392029"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/1157"],["dc.identifier.url","https://sfb1002.med.uni-goettingen.de/production/literature/publications/117"],["dc.notes.intern","WoS Import 2017-03-10"],["dc.notes.status","final"],["dc.notes.submitter","PUB_WoS_Import"],["dc.relation","SFB 1002: Modulatorische Einheiten bei Herzinsuffizienz"],["dc.relation","SFB 1002 | C02: RhoGTPasen und ihre Bedeutung für die Last-abhängige Myokardfibrose"],["dc.relation","SFB 1002 | C04: Fibroblasten-Kardiomyozyten Interaktion im gesunden und erkrankten Herzen: Mechanismen und therapeutische Interventionen bei Kardiofibroblastopathien"],["dc.relation.eissn","1095-8584"],["dc.relation.issn","0022-2828"],["dc.relation.workinggroup","RG Hasenfuß (Transition zur Herzinsuffizienz)"],["dc.relation.workinggroup","RG Lutz (G Protein-Coupled Receptor Mediated Signaling)"],["dc.relation.workinggroup","RG Tiburcy (Stem Cell Disease Modeling)"],["dc.relation.workinggroup","RG Toischer (Kardiales Remodeling)"],["dc.relation.workinggroup","RG Zimmermann (Engineered Human Myocardium)"],["dc.title","p63RhoGEF regulates auto- and paracrine signaling in cardiac fibroblasts"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.peerReviewed","yes"],["dc.type.subtype","original_ja"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.firstpage","630"],["dc.bibliographiccitation.issue","3"],["dc.bibliographiccitation.journal","Cellular Signalling"],["dc.bibliographiccitation.lastpage","638"],["dc.bibliographiccitation.volume","25"],["dc.contributor.author","Lutz, Susanne"],["dc.contributor.author","Mohl, Marion"],["dc.contributor.author","Rauch, Julia"],["dc.contributor.author","Weber, Pamina"],["dc.contributor.author","Wieland, Thomas"],["dc.date.accessioned","2018-11-07T09:27:35Z"],["dc.date.available","2018-11-07T09:27:35Z"],["dc.date.issued","2013"],["dc.description.abstract","RhoGEF17, the product of the ARHGEF17 gene, is a Rho-specific guanine nucleotide exchange factor (GEF) with an unusual structure and so far unknown function. In order to get insights in its regulation, we studied a variety of signaling pathways for activation of recombinantly expressed RhoGEF17. We found that in the presence of stable cGMP analogs RhoGEF17 associates with and is phosphorylated by co-expressed cGKI alpha at distinct phosphorylation sites leading to a cooperative activation of RhoA, the Rho dependent kinases (ROCK) and serum response factor-induced gene transcription. Activation of protein kinase A did not induce phosphorylation of RhoGEF17 nor altered its activity. Furthermore, we obtained evidence. for a ROCK-driven positive feedback mechanism involving serine/threonine protein phosphatases, which further enhanced cGMP/cGKI alpha-induced RhoGEF17 activation. By using mutants of RhoA which are phosphorylation resistant to cGK or mimic phosphorylation at serine 188, we could show that RhoGEF17 is able to activate RhoA independently of its phosphorylation state. Together with the ROCK-enforced activation of RhoGEF17 by cGMP/cGKI alpha, this might explain why expression of RhoGEF17 switches the inhibitory effect of cGMP/cGKI alpha on serum-induced RhoA activation into a stimulatory one. We conclude that RhoGEF17, depending on its expression profile and level, might drastically alter the effect of cGMP/cGK involving signaling pathways on RhoA-activated downstream effectors. (C) 2012 Elsevier Inc. All rights reserved."],["dc.description.sponsorship","Deutsche Forschungsgemeinschaft [Sonder-forschungsbereich/TransRegio 23]"],["dc.identifier.doi","10.1016/j.cellsig.2012.11.016"],["dc.identifier.isi","000315932000006"],["dc.identifier.pmid","23195829"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/30571"],["dc.notes.status","zu prüfen"],["dc.notes.submitter","Najko"],["dc.publisher","Elsevier Science Inc"],["dc.relation.issn","0898-6568"],["dc.title","RhoGEF17, a Rho-specific guanine nucleotide exchange factor activated by phosphorylation via cyclic GMP-dependent kinase I alpha"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.peerReviewed","yes"],["dc.type.status","published"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.firstpage","131"],["dc.bibliographiccitation.journal","Biochemical Journal"],["dc.bibliographiccitation.lastpage","140"],["dc.bibliographiccitation.volume","458"],["dc.contributor.author","Bodmann, Eva-Lisa"],["dc.contributor.author","Rinne, Andreas"],["dc.contributor.author","Brandt, Dominique"],["dc.contributor.author","Lutz, Susanne"],["dc.contributor.author","Wieland, Thomas"],["dc.contributor.author","Grosse, Robert"],["dc.contributor.author","Buenemann, Moritz"],["dc.date.accessioned","2018-11-07T09:43:44Z"],["dc.date.available","2018-11-07T09:43:44Z"],["dc.date.issued","2014"],["dc.description.abstract","Some G-protein-coupled receptors regulate biological processes via G alpha(12/13)- or G alpha(q/11)-mediated stimulation of RhoGEFs (guanine-nucleotide-exchange factors). p63RhoGEF is known to be specifically activated by G alpha(q/11) and mediates a major part of the acute response of vascular smooth muscle cells to angiotensin II treatment. In order to gain information about the dynamics of receptor-mediated activation of p63RhoGEF, we developed a FRET-based assay to study interactions between G alpha(q)-CFP and Venus-p63RhoGEF in single living cells. Upon activation of histaminergic H-1 or muscarinic M-3 receptors, a robust FRET signal occurred that allowed for the first time the analysis of the kinetics of this interaction in detail. On- and off-set kinetics of G alpha(q)-p63RhoGEF interactions closely resembled the kinetics of G alpha(q) activity. Analysis of the effect of RGS2 (regulator of G-protein signalling 2) on the dynamics of G alpha(q) activity and their interaction with p63RhoGEF showed that RGS2 is able to accelerate both deactivation of G alpha(q) proteins and dissociation of G alpha(q) and p63RhoGEF to a similar extent. Furthermore, we were able to detect activation-dependent FRET between RGS2 and p63RhoGEF and observed a reduced p63RhoGEF-mediated downstream signalling in the presence of RGS2. In summary, these observations support the concept of a functional activation-dependent p63RhoGEF-G alpha(q-)RGS2 complex."],["dc.description.sponsorship","Deutsche Forschungsgemeinschaft [SFB593]"],["dc.identifier.doi","10.1042/BJ20130782"],["dc.identifier.isi","000333718200012"],["dc.identifier.pmid","24299002"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/34242"],["dc.notes.status","zu prüfen"],["dc.notes.submitter","Najko"],["dc.publisher","Portland Press Ltd"],["dc.relation.issn","1470-8728"],["dc.relation.issn","0264-6021"],["dc.title","Dynamics of G alpha(q)-protein-p63RhoGEF interaction and its regulation by RGS2"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.peerReviewed","yes"],["dc.type.status","published"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.artnumber","15"],["dc.bibliographiccitation.issue","1"],["dc.bibliographiccitation.journal","Basic Research in Cardiology"],["dc.bibliographiccitation.volume","117"],["dc.contributor.author","Dewenter, Matthias"],["dc.contributor.author","Pan, Jianyuan"],["dc.contributor.author","Knödler, Laura"],["dc.contributor.author","Tzschöckel, Niklas"],["dc.contributor.author","Henrich, Julian"],["dc.contributor.author","Cordero, Julio"],["dc.contributor.author","Dobreva, Gergana"],["dc.contributor.author","Lutz, Susanne"],["dc.contributor.author","Backs, Johannes"],["dc.contributor.author","Wieland, Thomas"],["dc.contributor.author","Vettel, Christiane"],["dc.date.accessioned","2022-04-01T10:01:09Z"],["dc.date.available","2022-04-01T10:01:09Z"],["dc.date.issued","2022"],["dc.description.abstract","Abstract Hyperactivity of the sympathetic nervous system is a major driver of cardiac remodeling, exerting its effects through both α-, and β-adrenoceptors (α-, β-ARs). As the relative contribution of subtype α 1 -AR to cardiac stress responses remains poorly investigated, we subjected mice to either subcutaneous perfusion with the β-AR agonist isoprenaline (ISO, 30 mg/kg × day) or to a combination of ISO and the stable α 1 -AR agonist phenylephrine (ISO/PE, 30 mg/kg × day each). Telemetry analysis revealed similar hemodynamic responses under both ISO and ISO/PE treatment i.e., permanently increased heart rates and only transient decreases in mean blood pressure during the first 24 h. Echocardiography and single cell analysis after 1 week of exposure showed that ISO/PE-, but not ISO-treated animals established α 1 -AR-mediated inotropic responsiveness to acute adrenergic stimulation. Morphologically, additional PE perfusion limited concentric cardiomyocyte growth and enhanced cardiac collagen deposition during 7 days of treatment. Time-course analysis demonstrated a diverging development in transcriptional patterns at day 4 of treatment i.e., increased expression of selected marker genes Xirp2, Nppa, Tgfb1, Col1a1, Postn under chronic ISO/PE treatment which was either less pronounced or absent in the ISO group. Transcriptome analyses at day 4 via RNA sequencing demonstrated that additional PE treatment caused a marked upregulation of genes allocated to extracellular matrix and fiber organization along with a more pronounced downregulation of genes involved in metabolic processes, muscle adaptation and cardiac electrophysiology. Consistently, transcriptome changes under ISO/PE challenge more effectively recapitulated early transcriptional alterations in pressure overload-induced experimental heart failure and in human hypertrophic cardiomyopathy."],["dc.identifier.doi","10.1007/s00395-022-00920-z"],["dc.identifier.pii","920"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/105612"],["dc.language.iso","en"],["dc.notes.intern","DOI-Import GROB-530"],["dc.relation.eissn","1435-1803"],["dc.relation.issn","0300-8428"],["dc.rights.uri","https://creativecommons.org/licenses/by/4.0"],["dc.title","Chronic isoprenaline/phenylephrine vs. exclusive isoprenaline stimulation in mice: critical contribution of alpha1-adrenoceptors to early cardiac stress responses"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.firstpage","459"],["dc.bibliographiccitation.issue","6"],["dc.bibliographiccitation.journal","Naunyn-Schmiedeberg s Archives of Pharmacology"],["dc.bibliographiccitation.lastpage","469"],["dc.bibliographiccitation.volume","386"],["dc.contributor.author","Hippe, Hans-Joerg"],["dc.contributor.author","Luedde, Mark"],["dc.contributor.author","Schnoes, Katrin"],["dc.contributor.author","Novakovic, Ana"],["dc.contributor.author","Lutz, Susanne"],["dc.contributor.author","Katus, Hugo A."],["dc.contributor.author","Niroomand, Feraydoon"],["dc.contributor.author","Nuernberg, Bernd"],["dc.contributor.author","Frey, Norbert"],["dc.contributor.author","Wieland, Thomas"],["dc.date.accessioned","2018-11-07T09:24:25Z"],["dc.date.available","2018-11-07T09:24:25Z"],["dc.date.issued","2013"],["dc.description.abstract","Heterotrimeric G proteins are key regulators of signaling pathways in mammalian cells. Beyond G protein-coupled receptors, the amount and mutual ratio of specific G protein alpha, beta, and gamma subunits determine the G protein signaling. However, little is known about mechanisms that regulate the concentration and composition of G protein subunits at the plasma membrane. Here, we show a novel cross-talk between stimulatory and inhibitory G protein alpha subunits (G alpha) that is mediated by G protein beta gamma dimers and controls the abundance of specific G alpha subunits at the plasma membrane. Firstly, we observed in heart tissue from constitutively G alpha i2- and G alpha i3-deficient mice that the loss of G alpha i2 and G alpha i3 was accompanied by a slight increase in the protein content of the nontargeted G alpha i isoform. Therefore, we analyzed whether overexpression of selected G alpha subunits conversely impairs endogenous G protein alpha and beta subunit levels in cardiomyocytes. Integration of overexpressed G alpha i2 subunits into heterotrimeric G proteins was verified by co-immunoprecipitation. Adenoviral expression of increasing amounts of G alpha i2 led to a reduction of G alpha i3 (up to 90 %) and G alpha s (up to 75 %) protein levels. Likewise, increasing amounts of adenovirally expressed G alpha s resulted in a linear 75 % decrease in both G alpha i2 and G alpha i3 protein levels. In contrast, overexpression of either G alpha i or G alpha s isoform did not influence the amount of G alpha o and G alpha q, both of which are not involved in the regulation of adenylyl cyclase activity. The mRNA expression of the disappearing endogenous G alpha subunits was not affected, indicating a posttranslational mechanism. Interestingly, the amount of endogenous G protein beta gamma dimers was not altered by any G alpha overexpression. However, the increase of G beta gamma level by adenoviral expression prevented the loss of endogenous G alpha s and G alpha i3 in G alpha i2 overexpressing cardiomyocytes. Thus, our results provide evidence for a novel mechanism cross-regulating adenylyl cyclase-modulating G alpha i isoforms and G alpha s proteins. The G alpha subunits apparently compete for a limited amount of G beta gamma dimers, which are required for G protein heterotrimer formation at the plasma membrane."],["dc.identifier.doi","10.1007/s00210-013-0876-x"],["dc.identifier.isi","000318870700002"],["dc.identifier.pmid","23615874"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/29818"],["dc.notes.status","zu prüfen"],["dc.notes.submitter","Najko"],["dc.publisher","Springer"],["dc.relation.issn","0028-1298"],["dc.title","Competition for G beta gamma dimers mediates a specific cross-talk between stimulatory and inhibitory G protein alpha subunits of the adenylyl cyclase in cardiomyocytes"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.peerReviewed","yes"],["dc.type.status","published"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.firstpage","881"],["dc.bibliographiccitation.issue","9"],["dc.bibliographiccitation.journal","Circulation"],["dc.bibliographiccitation.lastpage","897"],["dc.bibliographiccitation.volume","135"],["dc.contributor.author","Abu-Taha, Issam H."],["dc.contributor.author","Heijman, Jordi"],["dc.contributor.author","Hippe, Hans-Jörg"],["dc.contributor.author","Wolf, Nadine M."],["dc.contributor.author","El-Armouche, Ali"],["dc.contributor.author","Nikolaev, Viacheslav O."],["dc.contributor.author","Schäfer, Marina"],["dc.contributor.author","Würtz, Christina M."],["dc.contributor.author","Neef, Stefan"],["dc.contributor.author","Voigt, Niels"],["dc.contributor.author","Baczkó, István"],["dc.contributor.author","Varró, András"],["dc.contributor.author","Müller, Marion"],["dc.contributor.author","Meder, Benjamin"],["dc.contributor.author","Katus, Hugo A."],["dc.contributor.author","Spiger, Katharina"],["dc.contributor.author","Vettel, Christiane"],["dc.contributor.author","Lehmann, Lorenz H."],["dc.contributor.author","Backs, Johannes"],["dc.contributor.author","Skolnik, Edward Y."],["dc.contributor.author","Lutz, Susanne"],["dc.contributor.author","Dobrev, Dobromir"],["dc.contributor.author","Wieland, Thomas"],["dc.date.accessioned","2020-12-10T18:38:01Z"],["dc.date.available","2020-12-10T18:38:01Z"],["dc.date.issued","2017"],["dc.description.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."],["dc.identifier.doi","10.1161/CIRCULATIONAHA.116.022852"],["dc.identifier.eissn","1524-4539"],["dc.identifier.isi","000395549700016"],["dc.identifier.issn","0009-7322"],["dc.identifier.pmid","27927712"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/77166"],["dc.language.iso","en"],["dc.notes.intern","DOI Import GROB-354"],["dc.notes.status","zu prüfen"],["dc.notes.submitter","PUB_WoS_Import"],["dc.publisher","Lippincott Williams & Wilkins"],["dc.relation.issn","1524-4539"],["dc.relation.issn","0009-7322"],["dc.title","Nucleoside Diphosphate Kinase-C Suppresses cAMP Formation in Human Heart Failure"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.peerReviewed","yes"],["dc.type.status","published"],["dspace.entity.type","Publication"]]