© 2001 by European Society of Cardiology
Copyright © 2000, European Society of Cardiology
Increased activity of membrane-associated nucleoside diphosphate kinase and inhibition of cAMP synthesis in failing human myocardium
aUniversity of Heidelberg, Department of Cardiology, Bergheimer Strasse 58, D-69115 Heidelberg, Germany
bSpecialty Care, VA Salt Lake City Health Care System, and Departments of Internal Medicine (Cardiology) and Pharmacology, University of Utah School of Medicine, Salt Lake City, UT, USA
* Corresponding author. Tel.: +49-6221-568-611; fax: +49-6221-565-515 feraydoon_niroomand{at}med.uni-heidelberg.de
Received 19 May 2000; accepted 1 September 2000
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Abstract |
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 Top Abstract 1 Introduction2 Methods3 Results4 DiscussionAcknowledgmentsReferences |
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Objective: Chronic heart failure is associated with a decreased responsiveness of the heart to β-adrenergic receptor agonists. We recently demonstrated a receptor-independent activation of G proteins and modulation of cardiac adenylyl cyclase activity by sarcolemmal membrane-associated nucleoside diphosphate kinase. We wondered whether changes in the activity of nucleoside diphosphate kinase occur in heart failure and contribute to or compensate for the impairment in myocardial receptor-mediated cAMP generation. Methods: Sarcolemmal membranes were purified from non-failing and failing human left ventricular myocardium. The protein level and activity of nucleoside diphosphate kinase were quantified. The influence of nucleoside diphosphate kinase on adenylyl cyclase activity was determined by measuring the effect of GDP on adenylyl cyclase activity in the absence and presence of nucleoside diphosphate kinase inhibitors. Results: The amount and activity of nucleoside diphosphate kinase in sarcolemmal membranes from failing hearts (n = 13) were increased 3- to 4-fold compared to levels in membranes from non-failing myocardium (n = 5). This increase in sarcolemmal nucleoside diphosphate kinase activity resulted in a 50% inhibition of adenylyl cyclase activity over a range of GDP and ATP concentrations. Conclusion: 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.
KEYWORDS G-proteins; Heart failure; Sarcolemma; Second messengers; Signal transduction
This article is referred to in the Editorial by Y.Y. Zhou and M. Artman (pages 7–10) in this issue.
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1 Introduction |
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TopAbstract1 Introduction2 Methods3 Results4 DiscussionAcknowledgmentsReferences |
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In the heart, cAMP-mediated signal transduction is important in the regulation of contraction and relaxation. cAMP activates protein kinase A, which phosphorylates a number of proteins involved in intracellular Ca2+ homeostasis in cardiac myocytes. The effect of these phosphorylations is an increase in the speed and amplitude of intracellular Ca2+ transients and muscle contraction and relaxation [1]. In chronic heart failure, several mechanisms contribute to a decreased stimulation of cAMP synthesis by β-adrenergic receptor agonists [2–6]. This may lead to the disturbances of Ca2+-handling that have been described in failing myocardium [7].
Stimulation and inhibition of adenylyl cyclase are mediated by the guanine nucleotide-binding regulatory proteins (G proteins) Gs and Gi, respectively. Hormonal receptor agonists activate G proteins by inducing the release of GDP from and the binding of GTP to the 
subunit of the G protein. The G protein is inactivated by hydrolysis of bound GTP to GDP by an intrinsic GTPase activity [8–10]. We recently demonstrated a receptor-independent modulation of cardiac adenylyl cyclase activity by G proteins and membrane-associated nucleoside diphosphate kinase (the nm23 gene product) in the presence of ATP and GDP [11]. Nucleoside diphosphate kinase catalyzes a transfer of the terminal phosphate of 5'-triphosphate nucleotides to GDP of inactive G proteins, which leads to their activation (Scheme 1). Regarding the regulation of adenylyl cyclase, both stimulatory and inhibitory G proteins may be activated through this mechanism [12–14]. In canine myocardial sarcolemmal membranes, the net effect of nucleoside diphosphate kinase activity is a stimulation of adenylyl cyclase activity by approximately 70%, apparently due to a predominance of the stimulatory effect of Gs proteins that are activated through this mechanism [11].
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The role of nucleoside diphosphate kinase activity in human myocardium has never been examined. In view of the abnormalities in G protein-mediated cAMP generation in failing human myocardium, it seemed particularly important to determine whether changes in the activity of nucleoside diphosphate kinase occur in heart failure and contribute to or compensate for the impairment in myocardial receptor-mediated cAMP generation. For this reason, we measured the level and activity of nucleoside diphosphate kinase and its influence on adenylyl cyclase activity in non-failing and failing human myocardium.
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2 Methods |
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TopAbstract1 Introduction2 Methods3 Results4 DiscussionAcknowledgmentsReferences |
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2.1 Tissue source and purification of sarcolemmal membranes
Non-failing human myocardium from the free wall of the left ventricle was obtained from five organ donors with no apparent heart disease and normal left ventricular function (determined by echocardiography) for whom no suitable heart transplant recipients had been identified. Left ventricular myocardium of failing human hearts were obtained from 13 patients who underwent cardiac transplantation due to end-stage heart failure (NYHA III–IV, idiopathic dilated cardiomyopathy in ten, ischaemic heart disease in three patients). Left ventricular ejection fraction was determined by radionuclide ventriculography. All patients underwent cardiac catheterization prior to transplantation. Pulmonary arterial wedge pressure and cardiac index were determined every 6 months while patients awaited for transplantation (Table 1). All explanted hearts were placed on ice immediately and cut into 1x1 cm3 pieces that were stored at –80°C until use. Sarcolemmal membranes were prepared by homogenization and differential sedimentation from 3 g of myocardium (left ventricular free wall) of five non-failing and 13 failing hearts. Each heart from control and failing hearts was processed separately. In addition, pooled tissue from three of the five control hearts was prepared separately for the detailed evaluation of adenylyl cyclase activity at various nucleotide concentrations.
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Myocardial tissue was finely minced and homogenized with a Polytron homogenizer for 5 s, three times. Purified sarcolemmal membranes were prepared from particulate fractions [15]. 5'Nucleotidase activity was determined as marker of plasma membrane. Cytosolic fractions were prepared by centrifugation of supernatants from the homogenate at 100 000 g for 60 min. Residual particulate fractions refers to all membranous components of the myocardial tissue, separated from the purified sarcolemmal membranes. Membranes and the cytosol were frozen in liquid nitrogen and stored prior to use at –80°C.
The investigation conforms with the principles outlined in the Declaration of Helsinki.
2.2 Adenylyl cyclase activity
Adenylyl cyclase activity was determined by measuring the conversion of [-32P]ATP to [32P]cAMP [16]. The assay volume was 100 µl containing 0.1 mmol/l ATP (except where otherwise indicated) with 0.5– 5x106 cpm of [-32P] ATP (3000 Ci/mmol), respectively, 3 mmol/l MgCl2, 0.1 mmol/l cAMP, 1 mmol/l EDTA, 0.5 mmol/l dithiothreitol, 0.05 mg bovine serum albumin, and 75 mmol/l triethanolamine, pH 7.6. The membranes (2.5–3.0 µg protein) were preincubated with alamethicin for 20 min at 4°C at a 1:1 ratio (w/w) to unmask latent adenylyl cyclase activity. This peptide ionophore increases the accessibility of substrates to the adenylyl cyclase in sealed sarcolemmal vesicles without affecting the functional coupling to receptors [17]. The adenylyl cyclase reaction was started by the addition of membrane protein and continued for 10 min at 37°C. Since for the purpose of this study no ATP regenerating system could be included, we wanted to ensure that decomposition of ATP under the assay conditions was not affecting our determinations, and we tested for this by measuring ATP hydrolysis at various ATP concentrations. After 10 min of incubation, reactions were stopped by the addition of EDTA (10 mmol/l) and samples were placed on ice. Adenine nucleotides were separated by thin-layer chromatography as described below, but with KH2PO4 (750 mmol/l, pH 3.3) as running buffer. During 10 min at 37°C, 30, 14 and 9% (at 100, 500 and 1000 µmol/l, respectively) of ATP were hydrolyzed. However, under these conditions, basal enzyme activity remained stable during the entire incubation period. Protein was determined using the Bradford Bio-Rad dye-binding assay, with bovine serum albumin as standard.
2.3 Nucleoside diphosphate kinase activity
Nucleoside diphosphate kinase activity was determined, using [3H]GDP (100 µmol/l; 0.1 Ci/mmol) as substrate, under the conditions as used for measurement of adenylyl cyclase activity, except that only 0.3 µg protein were used to avoid substrate depletion. Under these conditions, enzyme activity remained stable during the entire incubation period. Reactions were stopped by the addition of 5 µl of 10% (w/v) sodiumdodecyl sulfate at time points within the linear range of enzyme activity. Aliquots of 10 µl (in 2-µl steps) were spotted onto polyethyleneimine–cellulose F thin-layer chromatographic plates. A mixture of GTP–GDP–GMP (3 mmol/l each, 10 µl) was run in parallel and used as marker. Chromatography was performed with 2 mol/l formic acid–1 mol/l LiCl (1:1) for 30 min at room temperature. The nucleotides were identified under UV light, the polyethyleneimine–cellulose was scraped off, and radioactivity was measured in 4 ml of a liquid scintillation cocktail (Aquasure, DuPont-New England Nuclear). The purity of all nucleotides was analyzed by thin-layer chromatography.
2.4 Immunoblots
Membrane-enriched and cytosolic fractions were suspended in SDS–buffer for SDS–polyacrylamide gel electrophoresis [18]. The separated proteins were transferred electrophoretically to nitrocellulose membranes and immunodetection was carried out using polyclonal antibodies against nucleoside diphosphate kinase, Gs or Gi (Santa Cruz Biotechnology, Santa Cruz, CA, USA). Binding of the primary antibody was visualized using a second antibody, conjugated with horseradish peroxidase, against the Fc fragment of the primary antibody. Autoradiographs were subjected to densitometric analysis. All densitometric readings were made within a linear range of protein-dependent absorbance.
2.5 Data analysis
All experiments were carried out in triplicate and were repeated three times. Values are given as means±standard deviation. For statistical analysis, a two-tailed Student's t-test was used. Differences in the dose–response curves (Fig. 4a) were analyzed by means of two-way ANOVA.
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, pool of three hearts) and three failing (
) human hearts. (B) Stimulation of adenylyl cyclase activity by GDP (100 µmol/l) at various ATP concentrations in controls (C, pool of three hearts) and three failing (HF) hearts. The different stimulatory effect of GDP in control and failing hearts was similar at each concentration of ATP. ***, P<0.0001; *, P<0.01. |
3 Results |
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TopAbstract1 Introduction2 Methods3 Results4 DiscussionAcknowledgmentsReferences |
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3.1 Membrane characteristics
5'-Nucleotidase activity was 20±2.3 and 22±3.5 µmolh–1mg–1 in preparations from controls and failing hearts, demonstrating a similar yield of sarcolemma in both groups. In agreement with previous findings, basal adenylyl cyclase activity was not different in the failing hearts (242±29 and 262±36 pmolmin–1mg–1, respectively) [19]. The amount of Gi
was increased by 34% in membranes from failing hearts, the difference however did not reach statistical significance, most likely due to the small sample size of the controls. Also in agreement with previous studies, the level of Gs showed no difference (Table 2).
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3.2 Level and activity of nucleoside diphosphate kinase
To determine the protein levels of nucleoside diphosphate kinase in different fractions of the membrane preparation, immunoblots were performed using a polyclonal antibody which recognizes both subtypes of nucleoside diphosphate kinase, termed H1 and H2. Whole tissue homogenates, cytosolic fractions, the purified sarcolemma and residual particulate fractions (which included all the particulate material except the purified sarcolemma) were analyzed. Compared to the H2 isoform, only negligible amounts of H1 could be detected. In homogenates, cytosols and the residual particulate fractions the levels of nucleoside diphosphate kinase were similar in controls and failing hearts (Fig. 1). In contrast, a four-fold increased level of nucleoside diphosphate kinase was detected in sarcolemmal membranes of failing human ventricular myocardium (Fig. 2).
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We also measured nucleoside diphosphate kinase catalytic activity in these preparations. As seen with the immunodetectable protein level of nucleoside diphosphate kinase, enzyme activity of the nucleoside diphosphate kinase was increased three-fold in the sarcolemmal fraction from failing hearts. In contrast, nucleoside diphosphate kinase activity was not increased in homogenates, cytosols or the residual particulate fractions of failing hearts (Fig. 3).
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3.3 Effect of nucleoside diphosphate kinase on adenylyl cyclase
We proceeded to examine the contribution of the increased level of nucleoside diphosphate kinase on adenylyl cyclase activity in sarcolemmal fractions of failing human myocardium. The complexity of the experiments needed to do this reflects the fact that GDP has two distinct effects on adenylyl cyclase activity: in the absence of nucleoside diphosphate kinase activity, GDP inactivates G proteins, typically resulting in a stimulation of adenylyl cyclase activity that may be due to suppression of a spontaneous activation of Gi proteins [13,20–23]. In the presence of nucleoside diphosphate kinase, however, the phosphorylation of GDP to GTP adds a second effect attributable to the activation of G proteins [11]. This second effect may be stimulatory or inhibitory depending upon the relative activation of Gs and Gi.
In the absence of nucleoside diphosphate kinase inhibitors, addition of GDP increased adenylyl cyclase activity in membranes from non-failing myocardium by 125±25%. The maximally effective concentration of GDP was 100 µmol/l, a concentration similar to the physiologic intracellular concentration. In contrast, addition of GDP led only to a 70±30% stimulation of adenylyl cyclase activity in membranes from failing myocardium (Figs. 4 and 5
). This difference in the effect of GDP in failing and non-failing hearts was also present at different concentrations of GDP and ATP (Fig. 4A and B).
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We proceeded to measure the effect of GDP on adenylyl cyclase activity in the presence of the competitive nucleoside diphosphate kinase inhibitor 8-Br-cAMP. Nucleoside diphosphate kinase in sarcolemmal membranes was inhibited by 4 mmol/l 8-Br-cAMP down to 15% of basal activity in membranes from failing and non-failing hearts (control: from 34±13.5 to 4.3±2.6; heart failure: from 134±30.7 to 20.5±8.1 nmolmin–1mg–1). In sarcolemmal preparations from both non-failing and failing hearts, this concentration of 8-Br-cAMP reduced adenylyl cyclase activity by 20%, regardless of whether Mg2+ or Mn2+ was used as co-substrate, consistent with a small G protein-independent inhibition of adenylyl cyclase activity; 8-Br-cAMP did not influence the stimulation of adenylyl cyclase by guanosine 5'-O-(2-thio)diphosphate (GDPβS), GTP, GTP plus isoprenaline, forskolin, or the inhibition by carbachol (not shown), indicating that it does not interfere with G protein-dependent adenylyl cyclase regulation. When nucleoside diphosphate kinase activity was inhibited by inclusion of 4 mmol/l 8-Br-cAMP, however, addition of GDP stimulated adenylyl cyclase activity in non-failing and failing hearts to a similar extent (Fig. 5). In order to ensure that this result was not being influenced by phosphodiesterase inhibition by 8-Br-cAMP, we measured adenylyl cyclase activity in the absence of 8-Br-cAMP and in the presence of 1 mmol/l IBMX. The latter did not influence the measurement of adenylyl cyclase activity, indicating that phosphodiesterase activity had a negligible effect on the measurement of adenylyl cyclase activity under the assay conditions.
This result suggested that the diminished stimulation of adenylyl cyclase by GDP in sarcolemma from failing myocardium was attributable to an increased conversion of GDP to GTP by nucleoside diphosphate kinase. As a further test of this conclusion, we examined the stimulation of adenylyl cyclase activity by GDPβS, a GDP analog which binds to G proteins with effects similar to those of GDP but is a very poor substrate for nucleoside diphosphate kinase in these membranes. In contrast to the marked difference with respect to responses to GDP, the stimulation of adenylyl cyclase activity activity by GDPβS was similar in non-failing and failing human hearts (Fig. 5).
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4 Discussion |
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TopAbstract1 Introduction2 Methods3 Results4 DiscussionAcknowledgmentsReferences |
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Nucleoside diphosphate kinase has long been regarded as a ‘housekeeping’ enzyme essential for maintaining adequate levels of nucleoside triphosphates in the cell. Recently however, attention has been drawn to two other functional properties of this protein. First, several studies established a role for nucleoside diphosphate kinase in the regulation of cell differentiation and proliferation [24,25]. This effect of the nucleoside diphosphate kinase is independent of its enzymatic activity and appears to be due to its binding to nuclease hypersensitivity element, a regulatory domain for the transcription of DNA [26,27]. In addition, several reports have suggested that membrane-associated nucleoside diphosphate kinase has an important role in the receptor-independent activation of G proteins [12–14,28]. Our recent demonstration of receptor-independent but G protein-dependent modulation of adenylyl cyclase activity by nucleoside diphosphate kinase in sarcolemmal membranes from canine ventricular myocardium indicates that this may be a very important mechanism for modulating cAMP-dependent signal transduction in mammalian myocardium [11].
In the present study, we have demonstrated a 3- to 4-fold increase in the protein content and catalytic activity of membrane-associated nucleoside diphosphate kinase in sarcolemmal membranes of failing human hearts. The mechanism to which this increase is attributable is unclear: the fact that it is seen only in purified sarcolemmal membranes and not in the cytosol or other particulate fractions raises the possibility that an increase in the association of this enzyme with the sarcolemma rather than an increase in the transcription of the cognate gene or in the translation of the cognate RNA may be responsible. At this point, however, the factors that govern the intracellular distribution of this enzyme remain unknown. In addition, the possibility that there is a membrane-associated isoform of this enzyme that differs structurally from a closely related cytosolic form, as appears to occur in the case of PDE3 cyclic nucleotide phosphodiesterases [29,30], cannot be dismissed, although to date no evidence for this possibility has been reported.
Our experimental results demonstrate that the reduction in adenylyl cyclase activity we observed in failing myocardium in the presence of GDP is dependent on the conversion of GDP to GTP by nucleoside diphosphate kinase. Neither theoretical considerations nor any experimental data suggest that the activation of G proteins by nucleoside diphosphate kinase is selective with regard to the subtype of the -subunit. The effect of nucleoside diphosphate kinase activity on adenylyl cyclase activity should depend primarily on the prevalence of stimulatory and inhibitory G proteins, the amount and activity of the nucleoside diphosphate kinase and perhaps on membrane compartmentation. In canine myocardium, the net effect of nucleoside diphosphate kinase activity on the adenylyl cyclase was an increase in activity, since inhibition of nucleoside diphosphate kinase reduced adenylyl cyclase activity in the presence of GDP substantially [11]. In non-failing human myocardium, the fact that inhibition of nucleoside diphosphate kinase has little influence on adenylyl cyclase activity suggests that activation of stimulatory and inhibitory G proteins balance out. On the other hand, adenylyl cyclase activity in the presence of GDP is much lower in failing than in non-failing human myocardium, and inhibition of nucleoside diphosphate kinase causes a substantial increase in activity. Since G proteins are the only known target for an effect of guanine nucleotides on adenylyl cyclase activity, the decreased adenylyl cyclase activity in the presence of GTP (generated by the activity of nucleoside diphosphate kinase) should be due to an increased activation of Gi proteins. From our data, it is not possible to conclude whether the moderate increase in the density of Gi proteins in failing hearts contributes to this effect. The possibility that these differences between failing and non-failing hearts may be explained by an increased activation of Gi proteins through nucleoside diphosphate kinase activity in the failing hearts is consistent with all our results and is appealing in its simplicity. However, as a limitation of this study, we cannot prove this link, since no pharmacologic tools are available to specifically interrupt the interaction of nucleoside diphosphate kinase and Gi proteins.
Our observation that sarcolemmal nucleoside diphosphate kinase activity is markedly increased in failing myocardium, together with the evidence we have presented that this increase may contribute to an impairment in cAMP generation in failing human myocardium, is an important addition to our understanding of the molecular pathophysiology of impaired cAMP-mediated signal transduction in heart failure. That heart failure entails a downregulation of β-adrenergic receptors and an impairment in their coupling to adenylyl cyclase that reduces the response of failing myocardium to β-adrenergic receptor agonists has long been known [2]. Our results suggest that an increase in membrane-associated nucleoside diphosphate kinase leads to an increased receptor-independent activity of Gi proteins. The inhibition of adenylyl cyclase activity by nucleoside diphosphate kinase-catalyzed conversion of GDP to GTP may therefore contribute to a decrease in cAMP levels in failing hearts, and this may explain the decreased response of failing hearts to phosphodiesterase inhibitors as well as to β-adrenergic receptor agonists. It is tempting to speculate that an agent capable of selectively inhibiting myocardial sarcolemmal nucleoside diphosphate kinase activity might be a valuable addition to the inotropic therapy of heart failure.
Time for primary review 32 days.
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Acknowledgments |
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TopAbstract1 Introduction2 Methods3 Results4 DiscussionAcknowledgmentsReferences |
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Explanted failing human hearts were kindly provided by the Department of Cardiac Surgery, University of Heidelberg. This work was supported by the Deutsche Forschungsgemeinschaft, SFB 320/B1, and by the Office of Research and Development, Medical Research Service, United States Department of Veterans Affairs.
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