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Hypertension. 2004;43:1055-1059
Published online before print April 5, 2004, doi: 10.1161/01.hyp.0000126110.46402.dd
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(Hypertension. 2004;43:1055.)
© 2004 American Heart Association, Inc.

Scientific Contributions

Endogenous Diadenosine Tetraphosphate, Diadenosine Pentaphosphate, and Diadenosine Hexaphosphate in Human Myocardial Tissue

Jiankai Luo; Vera Jankowski; Nihayrt Güngär; Joachim Neumann; Wilhelm Schmitz; Walter Zidek; Hartmut Schlüter; Joachim Jankowski

From Medizinische Klinik IV (J.L., V.J., N.G., W.Z., H.S., J.J.), Charite-Campus Benjamin Franklin, Berlin, Germany, and Institut für Pharmakologie und Toxikologie (J.N., W.S.), Universität Münster, Germany. J.L. is currently at the Institute für Anatomie, Klinikum der Friedrich Schiller Universität Jena, Germany.

Correspondence to Dr J. Jankowski, Universitätsklinikum Benjamin Franklin, Freie Universität Berlin, Hindenburgdamm 30, D-12200 Berlin, Germany. E-mail Joachim.Jankowski{at}charite.de


*    Abstract
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 *Abstract
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Diadenosine polyphosphates have been characterized as extracellular mediators controlling numerous physiological effects. In this study, diadenosine tetraphosphate, diadenosine pentaphosphate, and diadenosine hexaphosphate were isolated and identified in human myocardial tissue. Human myocardial tissue was homogenized and fractionated by affinity chromatography, displacement chromatography, anion-exchange chromatography, and reversed-phase chromatography. In fractions purified to homogeneity, diadenosine tetraphosphate, diadenosine pentaphosphate, and diadenosine hexaphosphate were revealed by matrix-assisted laser desorption/ionization mass spectrometry and ultraviolet spectroscopy. These diadenosine polyphosphates were further identified by enzymatic analysis, which demonstrated an interconnection of the phosphate groups with the adenosines in the 5' positions of the riboses. Furthermore, diadenosine tetraphosphate, diadenosine pentaphosphate, and diadenosine hexaphosphate were found in human cardiac-specific granules, and the amount of diadenosine tetraphosphate, diadenosine pentaphosphate, and diadenosine hexaphosphate was estimated in the range of {approx}500 µmol/L. In conclusion, the experiments show that the diadenosine polyphosphates with 2 and 3 phosphate groups occur in human myocardial tissue, and so do the diadenosine polyphosphates with 4 to 6 phosphate groups. After being released by cholinergic stimulation, which is known to affect diadenosine polyphosphate release from secretory granules, diadenosine tetraphosphate, diadenosine pentaphosphate, and diadenosine hexaphosphate activate P2X purinoceptors in vascular smooth muscle; hence, they can act as vasoconstrictors. It may be inferred that the differential action of both predominantly vasodilator and vasoconstrictor diadenosine polyphosphates allow a fine-tuning of myocardial blood flow by locally released diadenosine polyphosphates.


Key Words: myocardium • cardiac function


*    Introduction
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Diadenosine polyphosphates (ApnA) have attracted growing interest in the past decade with respect to their roles in cardiovascular physiology and pathology.1–5 The actions of the ApnA within the cardiovascular system are mediated by the various purinoceptor subtypes. So far, 14 mammalian purinoceptor subtypes have been cloned,6,7 and 6 ApnAs containing 2 to 7 phosphate groups have been identified in humans.8–11 The affinities of a given ApnA to the various purinoceptor subtypes depends on the number of phosphate groups linking both adenosine moieties.9,12,13 Moreover, the purinoceptor subtypes are very differently distributed within the cardiovascular system. Depending on the purinoceptor subtypes activated in a given tissue, the ApnA are both vasoconstrictors and vasodilators,14,15 inhibitors and stimulators of platelet aggregation,8,9,11 and modulators of cell proliferation.9,11,16 Given this diversity of ApnA actions, it is not surprising that the ApnA actions reported in literature widely differ among various species. Currently, it is difficult to decide to what extent species-dependent differences in ApnA actions are caused by different purinoceptor distribution and to species-specificity of some of the known purinoceptor subtypes.

Obviously, local concentrations of ApnA are important determinants of ApnA-mediated effects.8,9 Hence, the local production of ApnA in the cardiovascular system has been studied recently. In earlier experiments, both Ap2A and Ap3A have been identified in human myocardial tissue.17 Both Ap2A and Ap3A have been characterized as vasodilators,14 whereas Ap4A, Ap5A, and Ap6A also have vasoconstricting properties,10,14 which increase with increasing number of phosphate groups.15 Therefore, it was of interest whether ApnA with >3 phosphate groups also occur in human myocardium. Given powerful local effects of these ApnA, because of high local concentrations, the presence of vasoconstrictive ApnA in human myocardium might have important consequences with respect to pathologic conditions such as myocardial infarction or excess sympathetic nerve stimulation, which is known to stimulate ApnA release from chromaffin granules. Therefore, in the present study, we examined whether ApnA are also present in human myocardium, which activate P2X purinoceptors in low concentrations and hence are powerful vasoconstrictors, ie, ApnA containing 4 to 6 phosphate groups. From earlier findings in the literature, this hypothesis appeared likely, because in chromaffin granules isolated from various tissues, several or all known types of ApnA occur.18–20 The experiments revealed that the ApnA acting predominantly as vasoconstrictors are also detectable in human myocardium.


*    Methods
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 *Methods
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Purification Procedures
Diadenosine polyphosphates were extracted from human myocardial tissue as described previously.17 The extract was concentrated by preparative reversed-phase chromatography (Lichroprep RP-18; 310x25 mm; Merck, Germany). The eluate of the preparative reversed-phase chromatography was fractionated by size-exclusion gel, preparative anion-exchange chromatography, preparative affinity chromatography, and reversed-phase chromatography. The chromatographic conditions were identical to the methods described previously;17 these conditions are also available in an online supplement at www.hyper.ahajournals.org.

Next, the desalted and lyophilized eluate of the affinity chromatography was dissolved in 40 mmol/L TEAA solution and was chromatographed by 2 connected reversed-phase columns (Supersphere 100 RP-18 end-capped; 300x8 mm; Merck) in the displacement mode.21 These reversed-phase columns were equilibrated with 40 mmol/L TEAA. The carrier (40 mmol/L TEAA) was pumped through the system at a flow rate of 100 µL/min during injection of the sample. After the injection, n-butanol (100 mmol/L in 40 mmol/L TEAA) was used as displacer (flow rate 100 µL/min). Each fraction (1 mL) was lyophilized and was further fractionated by anion-exchange chromatography.

The eluate of the displacement chromatography was fractionated by analytical anion-exchange chromatography (TSK DEAE-5PW; 75x7.5 mm; TosoHaas, Germany) and desalted by analytical reversed-phase chromatography (Supersphere 100 RP-18 end-capped; 100x2.1 mm, 4 µm; Merck).17

The lyophilized eluate of analytical reversed-phase chromatography was analyzed by matrix-assisted laser desorption/ionization (MALDI) mass spectrometry and postsource decay MALDI mass spectrometry using the conditions as described in Jankowski et al,22 UV spectroscopy,17 and enzymatic cleavage experiments.23

Identification of ApnA From Human Cardiac-Specific Granules
Diadenosine polyphosphates were isolated from specific granules of human left ventricular tissue according to the method of Luo et al.17


*    Results
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 *Results
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The extracts of human myocardial tissues were fractionated by size exclusion chromatography, anion-exchange chromatography, affinity chromatography, displacement chromatography, and analytic anion-exchange chromatography. Each fraction showing a significant UV absorption at 254 nm in the analytic anion-exchange chromatography was further chromatographed by reversed-phase chromatography. Each fraction with a significant absorbance at 254 nm of the reversed-phase high-performance liquid chromatography (HPLC) was further analyzed by mass spectrometric methods, UV spectroscopy, and enzymatic analysis.

Figure 1 shows a typical chromatogram of reversed-phase HPLC. The purified substances underlying the fractions labeled by arrows in the Figure were analyzed. By MALDI mass spectrometry, the molecular masses of these fractions (Figure 1) were revealed as 837.2 Da, 917.8 Da, and 997.4 Da [M+H]+, which correspond to Ap4A, Ap5A, and Ap6A. The UV spectra of these substances were characteristic of adenosine, with a maximum at 259 nm and minimum at 230 nm (data not shown). Moreover, the fragmentation patterns of the isolated substances were analyzed by postsource decay (PSD)-MALDI mass spectrometry.22,24



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  		Figure 1. Characteristic chromatograms of reversed-phase HPLC from an extract of human heart tissue after several chromatographies. The reversed-phase HPLC (column: Supersphere 100 RP-18 end-capped; 250' 4 mm; Merck, Germany) was performed with 40 mmol/L TEAA (eluent A) and 100% ACN (eluent B), and a gradient with eluent B (0 to 4 minutes, 0% to 2% B; 4 to 50 minutes, 2% to 7% B; 50 to 56 minutes, 7% to 60% B; 56 to 60 minutes, 60% to 80%) at a flow rate of 0.5 mL/min. The peaks labeled by arrows lead to the identification of Ap4A (A), Ap5A (B), and Ap6A (C), respectively.

The results show that the analyzed substances contained phosphate groups, adenosine, AMP, ADP, ATP, Ap4, or Ap5 (Table). The fragment patterns of the analyzed fractions were identical to those of authentic Ap4A, Ap5A, and Ap6A (Table). Furthermore, the interconnection of phosphate groups to the adenosines was analyzed by enzymatic analysis using alkaline phosphatase, 3'-nucleotide, and 5'-nucleotide hydrolase. Alkaline phosphatase and 3'-nucleotidase had no effect on these molecules (data not shown). The 5'-nucleotidase yielded AMP and ATP (Figure 2A) after incubation of the fraction labeled in Figure 1A, AMP and Ap4 (Figure 2B) after incubation of the fraction labeled in Figure 1B, and AMP and Ap5 (Figure 2C) after incubation of the fraction labeled in Figure 1C. The retention time in cleavage patterns is in accord with those of authentic Ap4A, Ap5A, and Ap6A. These results demonstrate that all adenosines in the purified molecules are interconnected via 5'-phosphodiester bonds of the riboses with the phosphates. In summary, by MALDI mass spectrometry, UV absorption analysis, PSD-MALDI mass spectrometry, and enzymatic analysis, the substances underlying the UV absorption peaks in the reversed-phase HPLC shown in Figure 1 were identified as Ap4A, Ap5A, and Ap6A.


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  		Mass Signals of the Fragment Ions (in mass/charge; m/z) Obtained by PSD-MALDI Mass Spectrometry of Each Diadenosine Polyphosphate Isolated From Human Myocardial Tissue



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  		Figure 2. Analytic anion-exchange chromatograms of the isolated diadenosine polyphosphates (labeled by arrows in A to C) after incubation with a 5'-nucleotidase. The analytic anion-exchange chromatographies (column: UnoQ-1; 7' 3.5 mm; BioRad) were performed at a flow rate of 0.5 mL/min with 20 mmol/L K2HPO4 (eluent A, pH 8.0) and 20 mmol/L K2HPO4 in 1 mol/L NaCl (eluent B, pH 8.0) by a gradient of 0 to 2 minutes, 0% B; 2 to 100 minutes, 0% to 40% B; 100 to 105 minutes, 40% to 100% B; and 105 to 116 minutes 100%.

To examine if Ap4A, Ap5A, and Ap6A are stored in granules, human ventricular-specific granules were isolated from myocardial tissue and the nucleotides were purified to homogeneity. Fractions from the reversed-phase HPLC were analyzed by MALDI mass spectrometry. Fractions with molecular masses of 837.8 Da, 917.3 Da, and 996.9 Da were analyzed by PSD-MALDI mass spectrometry. The fragmentation patterns were identical to authentic Ap4A, Ap5A, and Ap6A. Based on the UV absorption at 254 nm, and using Ap8A as internal standard and calibration curves of Ap4A, Ap5A, and Ap6A, the amount of Ap4A, Ap5A, and Ap6A in human myocardial-specific granules were estimated at {approx}500 µmol/L.


*    Discussion
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 *Discussion
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Whereas in earlier studies only Ap2A and Ap3A had been isolated from human myocardium,17 the present study shows that ApnA containing 4 to 6 phosphate moieties are also found in human myocardial tissue. Moreover, Ap4A, Ap5A, and Ap6A were identified in myocardial-specific granules, which are known to release their contents into the extracellular space after stimulation, eg, by cholinergic agonists.18,25 The concentrations of Ap4A, Ap5A, and Ap6A (see Results) in specific granules are not very different from those of Ap2A and Ap3A found earlier.17 Why had Ap4A, Ap5A, and Ap6A not been identified in our previous study?17 Most likely, methodological reasons may be responsible. The purification procedure in this study has been considerably improved with respect to the recovery of ApnA compared with the previous study. In this study, but not in the previous one, we used displacement chromatography before the analytic anion-exchange chromatography and reversed-phase HPLC. This procedure may be more effective to separate ApnA from myocardial tissue, because displacement chromatography has been shown to be a powerful method for separation of dinucleotide polyphosphates.26

From the presence of at least 5 different ApnAs in human myocardial tissue, it can be inferred that ApnA may have specific functions in human heart. What is the significance of these findings for cardiac physiology and pathology? To answer this question, the cardiovascular effects of ApnA have to be considered. Although presently our knowledge of the role of these molecules is still quite incomplete, animal experiments have given some hints as to potential physiological functions of these molecules. In the coronary vasculature of isolated hearts, Ap4A, Ap5A, and Ap6A induce species-dependent and dose-dependent vasodilation, which are mediated by release of either nitric oxide (NO) or prostacyclin (PGI2). These vasodilations are partially prevented or converted to a vasoconstriction after inhibition of NO or PGI2 production.27–29 Regarding electrophysiological effects on isolated hearts, Ap4A, Ap5A, and Ap6A increase action potential duration and refractory period, both effects being mediated by release of NO and PGI2.28 In guinea pig left atria, Ap4A, Ap5A, and Ap6A inhibited the positive inotropic response elicited by electrical stimulation.30,31 After beta-adrenergic stimulation, Ap4A and Ap6A exert negative chronotropic and inotropic effects in animals and human ventricular preparations. In contrast, Ap4A alone can exert positive inotropic effects.31,32 In physiologically relevant concentrations, Ap4A, Ap5A, and Ap6A may serve as endogenous modulators of ryanodine receptor-gated Ca2+ release channels in membranes prepared from rat cardiac muscle.33 Furthermore, Ap4A, Ap5A, and Ap6A are potent inhibitors of myocardial KATP channels.34–37

The concentration of Ap4A in coronary venous blood is increased during ischemia and reperfusion of heart, whereas it cannot be detected with normal oxygen supply.35 This increase of Ap4A during ischemia is probably caused by the release of Ap4A stored in myocardial-specific granules and activated platelets in blood.38 Ap4A reduces cardiac infarct size and reperfusion injury in the ischemic canine heart. Furthermore, Ap4A mimics cardioprotective effect of ischemic preconditioning in the rat heart and significantly improves the postischemic recovery of cardiac function, reducing the leakage of serum creatine kinase.39 Ap4A has cardioprotective effects on hypothermic heart storage and cardioplegia.40,41

Some of these effects of Ap4A appear to be mediated by activating protein kinase C and mitochondrial KATP channels via P2 years mimicking, in part, the effects of ischemic preconditioning.42 Moreover, Ap4A is an intracellular regulator ligand of the sarcolemmal KATP channel.42,43 Therefore, the intracellular Ap4A may directly interact with the mitochondrial KATP channel or is released to extracellular spaces and interacts with adjacent cells.

Ap5A was shown to bind to the nucleotide-binding domain of the myocardial KATP channel,43 thus decreasing channel opening probability. The ischemia-induced decreased Ap5A levels may thus contribute to open the KATP channel under ischemic conditions. The KATP channel is known to be a sensor of metabolic stress, especially of cellular hypoxia: With decreasing ATP concentrations, the opening probability of this channel increases. This may be an important mechanism for cells undergoing hypoxia to maintain membrane potential despite decreased function of transmembrane ion pumps such as the energy-dependent Na-K-ATPase.

The regulation of KATP channels appears to be only a small segment of the potential regulatory functions of myocardial ApnA. It may be assumed that Ap5A may have further effects on myocardial ion channels and purinoceptors, and so may the other ApnAs show regulatory effects, although differing according to the number of phosphate moieties. Taken together with the present findings, it may be inferred that the ApnA represent a new class of messengers in human myocardial cells, exhibiting cellular protective functions in metabolic or ischemic stress. Also, there are other still unknown effects that are dependent on their binding to purinoceptors and ion channels.

Perspectives
Given that the research on myocardial ApnA is at its very beginning, it is likely that changes in the patterns of ApnA levels associated with different metabolic or vascular disorders may have further still unknown effects in the pathophysiology of heart disease.


*    Acknowledgments
 
This work was supported by a grant of the DFG (Schl 406/1-2).

Received January 15, 2004; first decision February 2, 2004; accepted March 5, 2004.


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 *References
 

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01.hyp.0000126110.46402.ddv1
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