Increased activity of membrane-associated nucleoside diphosphate kinase and inhibition of cAMP synthesis in failing human myocardium

Lutz, Susanne; Mura, Roman; Baltus, Doris; Movsesian, Matthew A.; Kübler, W.; Niroomand, Feraydoon

doi:10.1016/s0008-6363(00)00222-4

Cited by 27 publications

(21 citation statements)

References 26 publications

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“…mRNA encoding two respiratory chain enzymes, ATP synthase (mitochondrial F1 complex) and nucleoside diphosphate kinase, was more abundant in LCR compared with HCR. This might be a compensatory mechanism to increase the energy production and has previously been reported in failing human hearts (31).…”

Section: Discussionmentioning

confidence: 54%

Aerobic capacity-dependent differences in cardiac gene expression

Bye

Langaas

Høydal

et al. 2008

Physiological Genomics

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Aerobic capacity is a strong predictor of cardiovascular mortality. To determine the relationship between inborn aerobic capacity and cardiac gene expression we examined genome-wide gene expression in hearts of rats artificially selected for high and low running capacity (HCR and LCR, respectively) over 16 generations. The artificial selection of LCR caused accumulation of risk factors of cardiovascular disease similar to the metabolic syndrome seen in human, whereas HCR had markedly better cardiac function. We also studied alterations in gene expression in response to exercise training in these animals. Left ventricle gene expression of both sedentary and exercise-trained HCR and LCR was characterized by microarray and gene ontology analysis. Out of 28,000 screened genes, 1,540 were differentially expressed between sedentary HCR and LCR. Only one gene was found differentially expressed by exercise training, but this gene had unknown name and function. Sedentary HCR expressed higher amounts of genes involved in lipid metabolism, whereas sedentary LCR expressed higher amounts of the genes involved in glucose metabolism. This suggests a switch in cardiac energy substrate utilization from normal mitochondrial fatty acid ␤-oxidation in HCR to carbohydrate metabolism in LCR, an event that often occurs in diseased hearts. LCR were also associated with pathological growth signaling and cellular stress. Hypoxic conditions seemed to be a common source for several of these observations, triggering hypoxia-induced alterations of transcription. In conclusion, inborn high vs. low aerobic capacity was associated with differences in cardiac energy substrate, growth signaling, and cellular stress. metabolic syndrome; metabolism; hypoxia; V O2max; hypertrophy ALTHOUGH MAXIMAL OXYGEN UPTAKE (V O 2max ) is statistically linked with cardiovascular mortality (23, 36), the mechanistic nature of this association is unknown and difficult to explore in humans. Specifically, it is well defined that the continuum of heart function is linearly related with the level of V O 2max (39). Within the gene-environment interactions, inheritance may account for as much as 70% of the variation in aerobic capacity in human (7). Hence, genetic predisposition and inborn aerobic capacity are likely to contribute toward cardiovascular disease and mortality.Rats with different inborn running capacities have been artificially selected over generations to generate strains with genetically determined high or low intrinsic capacity (25). The evolved strains of high capacity runners (HCR) and low capacity runners (LCR) have a 30% difference in V O 2max (17). Selecting for low running capacity also resulted in accumulation of risk factors that predispose to cardiovascular disease. That is, LCR have features of the metabolic syndrome, whereas HCR show an athletic phenotype with markedly better cardiac and vascular function relative to LCR (17, 52). These models were generated expressly for efficient and invasive evaluation of cardiometabolic disease that can lea...

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Section: Discussionmentioning

confidence: 54%

Aerobic capacity-dependent differences in cardiac gene expression

Bye

Langaas

Høydal

et al. 2008

Physiological Genomics

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“…7A). There was a significant (p<0.05) down-regulation of transcripts involved in adenine nucleotide synthesis and conversion, such as Entpd2 (Ectonucleoside triphosphate diphosphohydrolase 2) and Nme3 (Nucleoside diphosphate kinase 3) [30,31], but only in the HdhQ150 mouse model (p<0.05) (Fig. 7B).…”

Section: Transcriptional Remodeling Of Genes Involved In the Synthesimentioning

confidence: 97%

An impaired metabolism of nucleotides underpins a novel mechanism of cardiac remodeling leading to Huntington's disease related cardiomyopathy

Toczek

Zielonka

Zukowska

et al. 2016

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

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Huntington's disease (HD) is mainly thought of as a neurological disease, but multiple epidemiological studies have demonstrated a number of cardiovascular events leading to heart failure in HD patients. Our recent studies showed an increased risk of heart contractile dysfunction and dilated cardiomyopathy in HD pre-clinical models. This could potentially involve metabolic remodeling, that is a typical feature of the failing heart, with reduced activities of high energy phosphate generating pathways. In this study, we sought to identify metabolic abnormalities leading to HD-related cardiomyopathy in pre-clinical and clinical settings. We found that HD mouse models developed a profound deterioration in cardiac energy equilibrium, despite AMP-activated protein kinase hyperphosphorylation. This was accompanied by a reduced glucose usage and a significant deregulation of genes involved in de novo purine biosynthesis, in conversion of adenine nucleotides, and in adenosine metabolism. Consequently, we observed increased levels of nucleotide catabolites such as inosine, hypoxanthine, xanthine and uric acid, in murine and human HD serum. These effects may be caused locally by mutant HTT, via gain or loss of function effects, or distally by a lack of trophic signals from central nerve stimulation. Either may lead to energy equilibrium imbalances in cardiac cells, with activation of nucleotide catabolism plus an inhibition of resynthesis. Our study suggests that future therapies should target cardiac mitochondrial dysfunction to ameliorate energetic dysfunction. Importantly, we describe the first set of biomarkers related to heart and skeletal muscle dysfunction in both pre-clinical and clinical HD settings.Keywords: Huntington's disease, cardiomyopathy, arrhythmia, energy imbalance, catabolism of nucleotides, heart failure 3 SUMMARY Huntington's disease (HD) is a fatal neurodegenerative disorder caused by a polyglutamine expansion in the huntingtin protein. HD-related cardiomyopathy has been widely described in different mouse models, however there is little known about the source of the pathological remodelling in HD hearts. We found that contractile dysfunction in HD settings might be caused by components of cellular energy imbalance, changes in catabolism of adenine nucleotides, steady-state internal redox derangements and an activation of AMPK, leading to a shift in the cardiac substrate preference. These changes were accompanied by increased concentrations of adenine nucleotide catabolites (inosine, hypoxanthine, xanthine and uric acid) and uridine in both HD mouse models and HD patients' plasma. These metabolites represent the first identified biomarkers related to striated muscle dysfunction in HD. Our study explores a mechanism that might lead to HD-related cardiomyopathy and opens new avenues for therapeutic treatments in HD. HIGHLIGHTS• Heart dysfunction in HD is caused by the altered metabolism of nucleotides in vivo • Altered energy imbalances may lead to heart malfunction in HD in vivo• Increased lev...

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“…[44][45][46] Expression of NDPK-C and membrane content of NDPK-B and NDPK-C are also increased in heart failure patients. 39,47,48 Furthermore, a similar increase in NDPK-C has also been observed in rats receiving isoprenaline via osmotic mini pumps for 4 days, mimicking the increased catecholamine levels in human heart failure, suggesting that these effects are a consequence of sympathetic stimulation. 39,49 The increased NDPK-C mRNA levels during long-term β-adrenoceptor stimulation might be due to activation of AP-2-and CREBP-binding sites in the mouse nme3 gene, which can regulate gene expression depending on cAMP levels.…”

Section: Alterations In Ndpk-mediated Regulation Of G-protein Signalimentioning

confidence: 56%

“…However, it has been suggested that NDPKs may also enhance G i signaling in patients, contributing to a switch from NDPK-mediated regulation of G s to G i in heart failure, which might contribute to the decreased cAMP and impaired contractility (Figure 3). 39,47 Recent far western blot experiments indeed confirmed that NDPK-C can shift its interaction from Gα s to Gα i or vice versa, depending on the relative expression of each protein. 39 Similarly, co-immunoprecipitation experiments have identified less Gα s and more Gα i2 in the NDPK-C precipitate in ventricular samples from end-stage heart failure patients compared with healthy controls, strongly suggesting a switch from predominant G s to G i signaling.…”

Section: Alterations In Ndpk-mediated Regulation Of G-protein Signalimentioning

confidence: 89%

Regulation of heterotrimeric G-protein signaling by NDPK/NME proteins and caveolins: an update

Abu-Taha

Heijman

Feng

et al. 2018

Laboratory Investigation

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Heterotrimeric G proteins are pivotal mediators of cellular signal transduction in eukaryotic cells and abnormal G-protein signaling plays an important role in numerous diseases. During the last two decades it has become evident that the activation status of heterotrimeric G proteins is both highly localized and strongly regulated by a number of factors, including a receptor-independent activation pathway of heterotrimeric G proteins that does not involve the classical GDP/GTP exchange and relies on nucleoside diphosphate kinases (NDPKs). NDPKs are NTP/NDP transphosphorylases encoded by the nme/nm23 genes that are involved in a variety of cellular events such as proliferation, migration, and apoptosis. They therefore contribute, for example, to tumor metastasis, angiogenesis, retinopathy, and heart failure. Interestingly, NDPKs are translocated and/or upregulated in human heart failure. Here we describe recent advances in the current understanding of NDPK functions and how they have an impact on local regulation of G-protein signaling.

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Increased activity of membrane-associated nucleoside diphosphate kinase and inhibition of cAMP synthesis in failing human myocardium

Abstract: The amount and activity of nucleoside diphosphate kinase are increased in sarcolemmal membranes of failing human myocardium, resulting in a substantial receptor-independent inhibition of adenylyl cyclase activity.

Cited by 27 publications

References 26 publications

Aerobic capacity-dependent differences in cardiac gene expression

Aerobic capacity-dependent differences in cardiac gene expression

An impaired metabolism of nucleotides underpins a novel mechanism of cardiac remodeling leading to Huntington's disease related cardiomyopathy

Regulation of heterotrimeric G-protein signaling by NDPK/NME proteins and caveolins: an update

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