Role of CD39 (NTPDase-1) in Thromboregulation, Cerebroprotection, and Cardioprotection

Marcus, Aaron J.; Broekman, M. Johan; Drosopoulos, Joan H.F.; Olson, Kim E.; Islam, Naziba; Pinsky, David J.; Levi, Roberto

doi:10.1055/s-2005-869528

Cited by 135 publications

(102 citation statements)

References 59 publications

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“…In addition to other tissues, prominent expression of NTPDase1 is observed on vascular endothelium. By hydrolyzing prothrombotic ADP, NTPDase1 maintains vascular fluidity and plays an important role as a modulator of vascular inflammation and thrombosis [46,47] as well as in cerebroprotection and cardioprotection [48]. It furthermore controls endothelial P2Y receptor-dependent vasorelaxation [49].…”

Section: General Properties and Functional Rolementioning

confidence: 99%

Cellular function and molecular structure of ecto-nucleotidases

Zimmermann

Zebisch

Sträter

2012

Purinergic Signalling

854

922

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Ecto-nucleotidases play a pivotal role in purinergic signal transmission. They hydrolyze extracellular nucleotides and thus can control their availability at purinergic P2 receptors. They generate extracellular nucleosides for cellular reuptake and salvage via nucleoside transporters of the plasma membrane. The extracellular adenosine formed acts as an agonist of purinergic P1 receptors. They also can produce and hydrolyze extracellular inorganic pyrophosphate that is of major relevance in the control of bone mineralization. This review discusses and compares four major groups of ectonucleotidases: the ecto-nucleoside triphosphate diphosphohydrolases, ecto-5′-nucleotidase, ecto-nucleotide pyrophosphatase/phosphodiesterases, and alkaline phosphatases. Only recently and based on crystal structures, detailed information regarding the spatial structures and catalytic mechanisms has become available for members of these four ecto-nucleotidase families. This permits detailed predictions of their catalytic mechanisms and a comparison between the individual enzyme groups. The review focuses on the principal biochemical, cell biological, catalytic, and structural properties of the enzymes and provides brief reference to tissue distribution, and physiological and pathophysiological functions.

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Section: General Properties and Functional Rolementioning

confidence: 99%

Cellular function and molecular structure of ecto-nucleotidases

Zimmermann

Zebisch

Sträter

2012

Purinergic Signalling

854

922

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“…1, [15][16][17] At present, only very little is known about the regulation of CD39 and whether regulated expression provides a physiologic role. [18][19][20] Several studies have suggested that CD39 contributes to the protective aspects of adenine nucleotide metabolism during hypoxia and ischemia. 13 For example, CD39 has been strongly implicated in thromboregulatory roles during stroke, 9,21 intestinal ischemia reperfusion, 22 and in protection from vascular leak during hypoxia.…”

Section: Introductionmentioning

confidence: 99%

Central role of Sp1-regulated CD39 in hypoxia/ischemia protection

Eltzschig

Köhler²,

Eckle

et al. 2009

Blood

208

177

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Hypoxia is common to several inflammatory diseases, where multiple cell types release adenine-nucleotides (particularly adenosine triphosphate/adenosine diphosphate). Adenosine triphosphate/adenosine diphosphate is metabolized to adenosine through a 2-step enzymatic reaction initiated by CD39 (ectonucleoside-triphosphatediphosphohydrolase-1). Thus, extracellular adenosine becomes available to regulate multiple inflammatory endpoints. Here, we hypothesized that hypoxia transcriptionally up-regulates CD39 expression. Initial studies revealed hypoxia-dependent increases in CD39 mRNA and immunoreactivity on endothelia. Examination of the human CD39 gene promoter identified a region important in hypoxia inducibility. Multiple levels of analysis, including site-directed mutagenesis, chromatin immunoprecipitation, and inhibition by antisense, revealed a critical role for transcription-factor Sp1 in hypoxiainduction of CD39. Using a combination of cd39 Ϫ/Ϫ mice and Sp1 small interfering RNA in in vivo cardiac ischemia models revealed Sp1-mediated induction of cardiac CD39 during myocardial ischemia. In summary, these results identify a novel Sp1-dependent regulatory pathway for CD39 and indicate the likelihood that CD39 is central to protective responses to hypoxia/ischemia. IntroductionCirculating or locally released nucleotides are rapidly metabolized by vascular cell surface ectoenzymes. 1,2 It is now accepted that the major pathway for extracellular hydrolysis of adenosine triphosphate (ATP) and adenosine diphosphate (ADP) is the ectonucleoside triphosphate diphosphohydrolase 1 (E-NTPDase1), 3 previously identified as ecto-ATPase, ecto-ATPDase, or CD39. 4,5 CD39 is expressed on the endothelium and inflammatory cells 6 and modulates vascular cell and platelet purinoreceptor activity by the sequential hydrolysis of extracellular ATP or ADP to adenosine monophosphate (AMP). 5,7 The thromboregulatory and antiinflammatory role of CD39 has been recently demonstrated by the generation of mutant mice with disruption of the CD39 gene, 8,9 and by a series of experiments where high levels of ATPDase expression are attained by administration of adenoviral vectors at injured tissue sites. [10][11][12] These and other studies indicate that ATP hydrolysis by CD39 provides a readily available extracellular source for adenine nucleotides during hypoxia/inflammation. 13,14 Surface-bound CD39 converts ATP/ADP to AMP, which in turn is enzymatically hydrolyzed by ecto-5Ј-nucleotidase (CD73) to adenosine (Ado). When generated extracellularly by this cascade, Ado can activate each of 4 7-transmembrane-spanning adenosine receptors or can be internalized through dipyridamole-sensitive carriers. 2 These pathways have been shown to regulate diverse physiologic and pathophysiologic outcomes. 1,[15][16][17] At present, only very little is known about the regulation of CD39 and whether regulated expression provides a physiologic role. [18][19][20] Several studies have suggested that CD39 contributes to the protective aspects of adenine nucleoti...

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“…This enzyme, expressed on the surface of leukocytes and endothelial cells, is responsible for serial phosphohydrolysis of extracellular ATP to ADP and further to AMP, by virtue of its ecto-ATPase and ecto-ADPase activity (22)(23)(24). Since ADP is a potent platelet agonist via P2Y 12 receptors, endothelial CD39-mediated dissipation of ADP serves as a critical negative regulator of platelet activation and recruitment (22)(23)(24)(25)(26)(27). By metabolizing extracellular ATP and ADP, CD39 provides natural protection from nucleotides released from the injured vasculature or activated platelets.…”

Section: Introductionmentioning

confidence: 99%