Cardiovascular Ecto -5′-Nucleotidase
2004; Lippincott Williams & Wilkins; Volume: 95; Issue: 8 Linguagem: Inglês
10.1161/01.res.0000146278.94064.4b
ISSN1524-4571
Autores Tópico(s)Neonatal Health and Biochemistry
ResumoHomeCirculation ResearchVol. 95, No. 8Cardiovascular Ecto-5′-Nucleotidase Free AccessEditorialPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessEditorialPDF/EPUBCardiovascular Ecto-5′-NucleotidaseAn End to 40 Years in the Wilderness? Ray A. Olsson Ray A. OlssonRay A. Olsson From the Suncoast-AHA Cardiovascular Research Laboratory, Departments of Internal Medicine and Pharmacology and Therapeutics, University of South Florida, Tampa, Fla. Originally published15 Oct 2004https://doi.org/10.1161/01.RES.0000146278.94064.4bCirculation Research. 2004;95:752–753Elsewhere in this issue, Koszalka et al1 add another chapter to the long-running saga of the significance of ecto-5′-nucleotidase (CD-73) in cardiovascular function, showing that this enzyme catalyzes the formation of adenosine in amounts sufficient to have important physiological effects. A brief sketch of the tortuous path to our present understanding of the role of this enzyme puts this work in perspective. It also illustrates how science evolves stepwise, testing hypotheses based on available evidence and modifying them to fit the new evidence. In the early 1960s, Berne2 and, independently, Gerlach et al3 showed that hypoxia stimulated adenosine production in the heart. Within a few years, histochemists showed phosphatase activity able to hydrolyze AMP on the surface of cardiac and skeletal muscle myocytes. At first this seemed to provide an explanation for the adenosine released from hypoxic heart muscle, but there was a serious problem. The enzyme was outside the cell, but its substrate, AMP, was in the cytoplasm, separated by a sarcolemma thought at the time to be impermeable to nucleotides. Theories advanced to resolve this dilemma included the idea that the ectoenzyme also had transport capacity, but this faltered for lack of direct evidence. There was little further progress for approximately a decade, in part because the discovery of nitric oxide-mediated vasodilation4 dispelled the notion that adenosine was "the" regulator of coronary vascular resistance. Then, Japanese and American workers isolated cytosolic nucleotidases, and Andrew Newby clinched the importance of the cytosolic enzyme by showing that leukocytes poisoned with 2-deoxyglucose still produced adenosine despite inactivation of the ectoenzyme by antibodies directed against it.5 Cloning the genes for the cytosolic enzyme in the late 1990s seemed the final step in establishing the cytosol as the site of adenosine production. By then, thinking about the function of CD73 had largely shifted to its role as a B lymphocyte adhesion molecule.6However, there were still inconsistencies in the evidence supporting a solely cytosolic origin of cardiac adenosine. Inhibitors of the equilibrative nucleoside transporter, which should prevent adenosine export from the site of its formation, actually augmented the accumulation of adenosine in the extracellular space. Measurements of the transmembrane gradient of adenosine concentration7 showed that the concentration is higher in the extracellular space, reflecting in part the efficiency of the incorporation of adenosine into the adenylate pool by adenosine kinase, the cytosolic enzyme that converts adenosine to AMP. The simplest explanation for such findings is that adenosine indeed forms outside cells and, in well-oxygenated hearts, the cytosolic compartment acts as a sink rather than as the source of adenosine leaving the heart.We now know that cells can release ATP and other adenine nucleotides through any of several kinds of channels or from within secretory granules such as those of platelets, whereupon several ecto-phosphatases8 degrade it to adenosine (Figure). The questions now become, "How important is the extracellular pathway of adenosine formation, and does that adenosine actually do anything?" Koszalka et al have now answered both. They found that although the ecto-enzyme accounts for only a minor fraction of cardiac 5′-nucleotidase activity, the adenosine it generates has a significant impact on basal vascular tone, hemostasis, and leukocyte adhesion. In other words, the enzyme not only regulates the function of cells in the walls of blood vessels but also regulates the function of the blood cells traversing them. Although the authors draw their conclusions very narrowly, CD73-catalyzed extracellular adenosine formation might be physiologically important in organs other than the heart and blood vessels. For example, a large body of evidence suggests that adenosine plays a key role in tubuloglomerular feedback.9 Although there is now persuasive evidence10 that ATP participates in this critical function, the blunting of the response by the CD73 inhibitor adenosine-α,β-methylene diphosphonate11 and almost complete loss of autoregulatory capacity in mice lacking the A1 adenosine receptor (A1AR−/−)12,13 or CD7314 suggests the ATP might serve as a substrate supporting adenosine production in addition to whatever role it might play as a primary signaling molecule.Download figureDownload PowerPointRoles of cytosolic and ecto-5′-nucleotidases in adenosine formation. AK indicates adenosine kinase; AP, unspecific alkaline phosphatase; APCs, ATP-permeable channels; ATPases, ATP-hydrolyzing enzymes; c-5′NP and e-5′-NP, cytosolic and ecto-5′- nucleotidases; eNT, equilibrative nucleoside transporter; MK, myokinase; NPP, nucleotide (pyro)phosphatases. The "stalks" connecting NPP, AP, and e5′-NP to the plasma membrane represent the peptide (NPP) and glycophosphatidylinositol chains (AP, e5′-NP) anchoring these enzymes to the membrane. For simplicity, this model does not include extracellular adenosine production from cAMP catalyzed by ecto-phosphodiesterase or production in the cytosol through the S-adenosylhomocysteine hydrolase pathway, both of which contribute to net adenosine production.Coronary resistance was slightly but significantly higher in the CD73−/− mice, suggesting that the small amount of adenosine generated by that pathway might still participate in setting basal coronary tone. Such is probably not the case during hypoxia, when hyperemia owes to the exuberant outpouring of adenosine resulting from a rapid, high-degree inhibition of recycling through adenosine kinase.15Recently, Colgan et al16 discovered another example of the involvement of CD73 in cardiovascular regulation. Activated neutrophils traversing the endothelial barrier release ATP, which undergoes sequential hydrolysis by CD39, a diphosphohydrolase, and CD73 to release adenosine, which then activates A2B adenosine receptors on the endothelial cells to seal the endothelial gap and restore barrier integrity.And there is more. Using immunohistochemistry, Koszalka et al showed that in addition to CD73, coronary microvessels contain low levels of unspecific alkaline phosphatase, another AMP-hydrolyzing ectoenzyme. The minor effect of the alkaline phosphatase inhibitor levamisole authoritatively established the primacy of CD73 in the extracellular formation of adenosine. Interestingly, the two enzymes occurred in different microvessels, adding to other evidence of the regional heterogeneity of vascular endothelial cells.By activating adenosine A2A receptors, adenosine suppresses the expression of cell adhesion molecules on both leukocytes and endothelial cells.17 This easily accounts for the increased monocyte adhesion the authors measured in CD73−/− mice (apparently, the function of CD73 as a leukocyte adhesion molecule is limited to B lymphocytes6). The same receptors on platelets antagonize activation by agents such as ADP and thrombin, likewise accounting for the impaired coagulation they measured in these mice.So, this elegant multidisciplinary (and multinational) study, which combined molecular biology, histochemistry, and coronary physiology, has shown that ecto-5′-nucleotidase is a very important player in cardiovascular physiology after all, although not in ways anyone imagined 40 years ago when Berne and Gerlach first floated the "adenosine hypothesis."The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.This work was supported by the Suncoast AHA Chapter–Wright Chair in Cardiovascular Research, University of South Florida. I am grateful to Professor Joel Linden, University of Virginia, for reading and commenting on this article.FootnotesCorrespondence to Ray A. Olsson, Department of Internal Medicine, MDC Box 19, 12901 Bruce B. Downs Blvd, Tampa, FL 33612. E-mail [email protected] References 1 Koszalka P, Özüyaman B, Huo Y, Zernecke A, Flögel U, Braun N, Buchheiser A, Decking UKM, Smith ML, Sévigny J, Gear A, Weber A-A, Molojavyi A, Ding Z, Weber C, Ley K, Zimmermann H, Gödecke A, Schrader J. Targeted disruption of cd73/ecto-5′-nucleotidase alters thromboregulation and augments vascular inflammatory response. Circ Res. 2004; 95: 814–821.LinkGoogle Scholar2 Berne RM. Cardiac nucleotides in hypoxia: possible role in regulation of coronary blood flow. Am J Physiol. 1963; 204: 317–322.CrossrefMedlineGoogle Scholar3 Gerlach E., Deuticke B., Dreisbach RH. Zum Verhalten von Nucleotiden und ihren dephosphorylierten Abbauprodukten in der Niere bei Ischämie und kurzzeitiger post-ischämischer Wiederdurchblutung. Pfugers Arch. 1963; 278: 296–315.CrossrefGoogle Scholar4 Furchgott RF, Zawadski JV. The obligatory role of endothelial cells in the relaxation of arterial smooth cells by acetylcholine. Nature. 1980; 288: 373–376.CrossrefMedlineGoogle Scholar5 Worku Y, Newby AC. The mechanism of adenosine production in polymorphonuclear leukocytes. Biochem J. 1988; 214: 325–330.Google Scholar6 Airas L, Niemelä J, Salmi M, Puurunen T, Smith DJ, Jalkanen S. Differential regulation and function of CD78, a glycophosphatidylinositol-linked 70-kD adhesion molecule, on lymphocytes and endothelial cells. J Cell Biol. 1997; 136: 421–431.CrossrefMedlineGoogle Scholar7 Deussen A, Stappert M, Schäfer S, Kelm M. Quantification of extracellular and intracellular adenosine production. Understanding the transmembranous concentration gradient. Circulation. 1999; 99: 2041–2047.CrossrefMedlineGoogle Scholar8 Zimmermann H. Ectonucleotidases: Some recent developments and a note on nomenclature. Drug Dev Res. 2001; 52: 44–56.CrossrefGoogle Scholar9 Kriz W. Adenosine and ATP: traffic regulators in the kidney. J Clin Invest. 2004; 114: 611–613.CrossrefMedlineGoogle Scholar10 Bell PD, Lapointe J-Y, Sabirov R, Hayashi S, Peti-Perdi J, Manabe K, Kovacs G, Okada Y. Macula densa signaling involves ATP release through a maxi anion channel. Proc Natl Acad Sci U S A. 2003; 100: 4322–4327.CrossrefMedlineGoogle Scholar11 Thompson S, Bao D, Deng A, Vallon V. Adenosine formed by 5′-nucleotidase mediates tubuloglomerular feedback. J Clin Invest. 2000; 106: 289–298.CrossrefMedlineGoogle Scholar12 Sun D, Samuelson LC, Yang T, Huang Y, Palliege A, Saunders T, Briggs J, Schnermann J. Mediation of tubulo-glomerular feedback by adenosine: Evidence from mice lacking adenosine 1 receptors. Proc Natl Acad Sci U S A. 2001; 98: 9983–9988.CrossrefMedlineGoogle Scholar13 Brown R, Ollerstam A, Johansson B, Skott O, Gebre-Medhin S. Fredholm, B, Persson E. Abolished tubulo-glomerular feedback and increased plasma renin in adenosine A1 receptor-deficient mice. Am J Physiol. 2001; 281: R1362–R1367.MedlineGoogle Scholar14 Castrop H, Huang Y, Hashimoto S, Mizel D, Hansen P, Thelig F, Bachmann S, Deng C, Schnermann J. Impairment of tubuloglomerular feedback regulation of GFR in ecto-5′-nucleotidase/CD73-deficient mice. J Clin Invest. 2004; 114: 634–642.CrossrefMedlineGoogle Scholar15 Decking UK, Schlieper G, Kroll K, Schrader J. Hypoxia-induced inhibition of adenosine kinase potentiates cardiac adenosine release. Circ Res. 1997; 81: 154–164.CrossrefMedlineGoogle Scholar16 Eltzschig HK, Ibla JC, Furuta GT, Leonard MO, Jacobson KA, Enjyoji K, Robson SC, Colgan SP. Coordinated adenine nucleotide phosphohydrolysis and nucleoside signaling in posthypoxic endothelium: Role of ectonucleotidases and adenosine A2B receptors. J Exp Med. 2003; 198: 783–796.CrossrefMedlineGoogle Scholar17 Sullivan GW. Adenosine A2A receptor agonists as anti-inflammatory agents. Curr Opin Investig Drugs. 2003; 4: 1313–1319.MedlineGoogle Scholar Previous Back to top Next FiguresReferencesRelatedDetailsCited By Minor M, Alcedo K, Battaglia R and Snider N (2019) Cell type- and tissue-specific functions of ecto-5′-nucleotidase (CD73), American Journal of Physiology-Cell Physiology, 10.1152/ajpcell.00285.2019, 317:6, (C1079-C1092), Online publication date: 1-Dec-2019. Burnstock G and Pelleg A (2014) Cardiac purinergic signalling in health and disease, Purinergic Signalling, 10.1007/s11302-014-9436-1, 11:1, (1-46), Online publication date: 1-Mar-2015. Nilsson K, Grishina V, Glaumann C and Gustafsson L (2010) Estimation of endogenous adenosine activity at adenosine receptors in guinea-pig ileum using a new pharmacological method, Acta Physiologica, 10.1111/j.1748-1716.2010.02090.x, 199:2, (231-241) Crane J and Shulgina I (2009) Feedback effects of host-derived adenosine on enteropathogenic Escherichia coli , FEMS Immunology & Medical Microbiology, 10.1111/j.1574-695X.2009.00598.x, 57:3, (214-228), Online publication date: 1-Dec-2009. Khalpey Z, Yuen A, Lavitrano M, McGregor C, Kalsi K, Yacoub M and Smolenski R (2007) Mammalian mismatches in nucleotide metabolism: implications for xenotransplantation, Molecular and Cellular Biochemistry, 10.1007/s11010-007-9491-9, 304:1-2, (109-117), Online publication date: 18-Sep-2007. Ogura K, Miake J, Sasaki N, Iwai C, Bahrudin U, Li P, Kato M, IItsuka K, Hirota Y, Koshida T, Yamamoto Y, Inoue Y, Yano A, Adachi M, Igawa O, Kurata Y, Morisaki T, Shiota G, Shirayoshi Y, Haruaki N and Hisatome I (2007) Inhibition of β-adrenergic signaling by intracellular AMP is independent of cell-surface adenosine receptors in rat cardiac cells, Journal of Molecular and Cellular Cardiology, 10.1016/j.yjmcc.2007.07.059, 43:5, (648-652), Online publication date: 1-Nov-2007. Crane J, Shulgina I and Naeher T (2007) Ecto-5′-nucleotidase and intestinal ion secretion by enteropathogenic Escherichia coli, Purinergic Signalling, 10.1007/s11302-007-9056-0, 3:3, (233-246), Online publication date: 1-Jun-2007. October 15, 2004Vol 95, Issue 8 Advertisement Article InformationMetrics https://doi.org/10.1161/01.RES.0000146278.94064.4bPMID: 15486321 Originally publishedOctober 15, 2004 Keywordscell adhesion moleculesadenosinecoronary flowecto-phosphatasesCD 73inflammationPDF download Advertisement
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