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Research ArticlePERSPECTIVES IN PHARMACOLOGY

Metabolic Control of Excessive Extracellular Nucleotide Accumulation by CD39/Ecto-Nucleotidase-1: Implications for Ischemic Vascular Diseases

Aaron J. Marcus, M. Johan Broekman, Joan H. F. Drosopoulos, Naziba Islam, David J. Pinsky, Casilde Sesti and Roberto Levi
Journal of Pharmacology and Experimental Therapeutics April 2003, 305 (1) 9-16; DOI: https://doi.org/10.1124/jpet.102.043729
Aaron J. Marcus
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M. Johan Broekman
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Joan H. F. Drosopoulos
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Naziba Islam
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David J. Pinsky
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Casilde Sesti
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Roberto Levi
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Abstract

Platelets are responsible for maintaining vascular integrity. In thrombocytopenic states, vascular permeability and fragility increase, presumably due to the absence of this platelet function. Chemical or physical injury to a blood vessel induces platelet activation and platelet recruitment. This is beneficial for the arrest of bleeding (hemostasis), but when an atherosclerotic plaque is ulcerated or fissured, it becomes an agonist for vascular occlusion (thrombosis). Experiments in the late 1980s cumulatively indicated that endothelial cell CD39—an ecto-ADPase—reduced platelet reactivity to most agonists, even in the absence of prostacyclin or nitric oxide. As discussed herein, CD39 rapidly and preferentially metabolizes ATP and ADP released from activated platelets to AMP, thereby drastically reducing or even abolishing platelet aggregation and recruitment. Since ADP is the final common agonist for platelet recruitment and thrombus formation, this finding highlights the significance of CD39. A recombinant, soluble form of human CD39, solCD39, has enzymatic and biological properties identical to the full-length form of the molecule and strongly inhibits human platelet aggregation induced by ADP, collagen, arachidonate, or TRAP (thrombin receptor agonist peptide). In sympathetic nerve endings isolated from guinea pig hearts, where neuronal ATP enhances norepinephrine exocytosis, solCD39 markedly attenuated norepinephrine release. This suggests that NTPDase (nucleoside triphosphate diphosphohydrolase) could exert a cardioprotective action by reducing ATP-mediated norepinephrine release, thereby offering a novel therapeutic approach to myocardial ischemia and its consequences. In a murine model of stroke, driven by excessive platelet recruitment, solCD39 reduced the sequelae of stroke, without an increase in intracerebral hemorrhage. CD39 null mice, generated by deletion of apyrase-conserved regions 2 to 4, exhibited a decrease in postischemic perfusion and an increase in cerebral infarct volume when compared with controls. “Reconstitution” of CD39 null mice with solCD39 reversed these changes. We hypothesize that solCD39 has potential as a novel therapeutic agent for thrombotic diatheses.

Footnotes

  • This study was supported by National Institutes of Health Grants HL47073, HL46403, and NS41462 (to A.J.M., M.J.B., J.H.F.D., and N.I.), NS41460, HL59488, and HL69448 (to D.J.P.), and HL34215 and HL46403 (to C.S. and R.L.), and by Merit Review grants from the Department of Veterans Affairs (to A.J.M., M.J.B., J.H.F.D., N.I.).

  • DOI: 10.1124/jpet.102.043729

  • Abbreviations:
    vWF
    von Willebrand Factor
    TXA2
    thromboxane A2
    PGI2
    prostaglandin I2
    HUVEC
    human umbilical vein endothelial cells
    ACR
    apyrase-conserved regions
    TRAP
    thrombin receptor agonist peptide
    PRP
    platelet-rich plasma
    NE
    norepinephrine
    PPADS
    pyridoxal phosphate-6-azophenyl-2′,4′-disulfonic acid
    ARL-67156
    6-N,N-diethyl-β-γ-dibromomethylene-d-adenosine-5′-triphosphate
    CD39
    cluster of differentiation number 39
    DEPC
    diethyl pyrocarbonate
    MRS-2179
    2′-deoxy-N6-methyladenosine-3′,5′-diphosphate
    NTPDase
    nucleoside triphosphate diphosphohydrolase
    • Received August 27, 2002.
    • Accepted November 15, 2002.
  • U.S. Government
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Journal of Pharmacology and Experimental Therapeutics: 305 (1)
Journal of Pharmacology and Experimental Therapeutics
Vol. 305, Issue 1
1 Apr 2003
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Research ArticlePERSPECTIVES IN PHARMACOLOGY

Metabolic Control of Excessive Extracellular Nucleotide Accumulation by CD39/Ecto-Nucleotidase-1: Implications for Ischemic Vascular Diseases

Aaron J. Marcus, M. Johan Broekman, Joan H. F. Drosopoulos, Naziba Islam, David J. Pinsky, Casilde Sesti and Roberto Levi
Journal of Pharmacology and Experimental Therapeutics April 1, 2003, 305 (1) 9-16; DOI: https://doi.org/10.1124/jpet.102.043729

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Research ArticlePERSPECTIVES IN PHARMACOLOGY

Metabolic Control of Excessive Extracellular Nucleotide Accumulation by CD39/Ecto-Nucleotidase-1: Implications for Ischemic Vascular Diseases

Aaron J. Marcus, M. Johan Broekman, Joan H. F. Drosopoulos, Naziba Islam, David J. Pinsky, Casilde Sesti and Roberto Levi
Journal of Pharmacology and Experimental Therapeutics April 1, 2003, 305 (1) 9-16; DOI: https://doi.org/10.1124/jpet.102.043729
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  • Article
    • Abstract
    • The Hemostatic Mechanism
    • Primary Hemostasis
    • Hemostasis and Thrombosis As Models of Cell-Cell Interactions
    • Ecto-ADPase/CD39 (NTPDase-1), the Major Inhibitor of Platelet Activation and Recruitment
    • Identification of CD39 As the Endothelial Cell Ecto-ADPase
    • SolCD39: The Recombinant Soluble Form of CD39/Ecto-ADPase
    • Site-Directed Mutagenesis Studies of Amino Acids in the ACR of SolCD39
    • Thromboregulation by CD39 in the Ischemic Brain
    • Ecto-Nucleotidase in Cardiac Sympathetic Nerves
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