JPET Assistant Professor of Medicine (Clinician-Educator)

Home Help [Feedback] [For Subscribers] [Archive] [Search] [Contents]
QUICK SEARCH:   [advanced]


     

Journal of Pharmacology And Experimental Therapeutics Fast Forward
First published on January 21, 2003; DOI: 10.1124/jpet.102.043729

This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow All Versions of this Article:
jpet.102.043729v1
305/1/9    most recent
Right arrow Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Marcus, A. J.
Right arrow Articles by Levi, R.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Marcus, A. J.
Right arrow Articles by Levi, R.
Right arrowPubmed/NCBI databases
*Substance via MeSH
Medline Plus Health Information
*Vascular Diseases

Vol. 305, Issue 1, 9-16, April 2003

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

Departments of Medicine (A.J.M., M.J.B., J.H.F., N.I.), Pathology (A.J.M.), and Pharmacology (C.S., R.L.); Weill Medical College of Cornell University, Medical Service/Hematology-Oncology (A.J.M., M.J.B., J.H.F., N.I.), Veterans Affairs New York Harbor Healthcare System, Division of Cardiology (D.J.P.) and Division of Circulatory Physiology (D.J.P.), Department of Medicine, College of Physicians and Surgeons, Columbia University, New York, New York

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.

0022-3565/03/3051-0009$00.00/0
THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
Copyright © 2003 by U.S. Government


This article has been cited by other articles:


Home page
 Cardiovasc ResHome page
K. H. Lin, G. Hsiao, C. M. Shih, D. S. Chou, and J. R. Sheu
Mechanisms of resveratrol-induced platelet apoptosis
Cardiovasc Res, June 8, 2009; (2009) cvp139v2.
[Abstract] [Full Text] [PDF]

Home page
 BloodHome page
H. K. Eltzschig, D. Kohler, T. Eckle, T. Kong, S. C. Robson, and S. P. Colgan
Central role of Sp1-regulated CD39 in hypoxia/ischemia protection
Blood, January 1, 2009; 113(1): 224 - 232.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
D.-J. Jun, J. Kim, S.-Y. Jung, R. Song, J.-H. Noh, Y.-S. Park, S.-H. Ryu, J.-H. Kim, Y.-Y. Kong, J.-M. Chung, et al.
Extracellular ATP Mediates Necrotic Cell Swelling in SN4741 Dopaminergic Neurons through P2X7 Receptors
J. Biol. Chem., December 28, 2007; 282(52): 37350 - 37358.
[Abstract] [Full Text] [PDF]

Home page
 J. Pharmacol. Exp. Ther.Home page
C. Medina, P. Jurasz, M. J. Santos-Martinez, S. S. Jeong, T. Mitsky, R. Chen, and M. W. Radomski
Platelet Aggregation-Induced by Caco-2 Cells: Regulation by Matrix Metalloproteinase-2 and Adenosine Diphosphate
J. Pharmacol. Exp. Ther., May 1, 2006; 317(2): 739 - 745.
[Abstract] [Full Text] [PDF]

Home page
 Pharmacol. Rev.Home page
G. Burnstock
Pathophysiology and therapeutic potential of purinergic signaling.
Pharmacol. Rev., March 1, 2006; 58(1): 58 - 86.
[Abstract] [Full Text] [PDF]

Home page
 HypertensionHome page
G. Silva, W. H. Beierwaltes, and J. L. Garvin
Extracellular ATP Stimulates NO Production in Rat Thick Ascending Limb
Hypertension, March 1, 2006; 47(3): 563 - 567.
[Abstract] [Full Text] [PDF]

Home page
 J. Pharmacol. Exp. Ther.Home page
T. Machida, P. M. Heerdt, A. C. Reid, U. Schafer, R. B. Silver, M. J. Broekman, A. J. Marcus, and R. Levi
Ectonucleoside Triphosphate Diphosphohydrolase1/CD39, Localized in Neurons of Human and Porcine Heart, Modulates ATP-Induced Norepinephrine Exocytosis
J. Pharmacol. Exp. Ther., May 1, 2005; 313(2): 570 - 577.
[Abstract] [Full Text] [PDF]

Home page
 CirculationHome page
E. Furukoji, M. Matsumoto, A. Yamashita, H. Yagi, Y. Sakurai, K. Marutsuka, K. Hatakeyama, K. Morishita, Y. Fujimura, S. Tamura, et al.
Adenovirus-Mediated Transfer of Human Placental Ectonucleoside Triphosphate Diphosphohydrolase to Vascular Smooth Muscle Cells Suppresses Platelet Aggregation In Vitro and Arterial Thrombus Formation In Vivo
Circulation, February 15, 2005; 111(6): 808 - 815.
[Abstract] [Full Text] [PDF]

Home page
 IOVSHome page
P. Gomes, S. P. Srinivas, J. Vereecke, and B. Himpens
ATP-Dependent Paracrine Intercellular Communication in Cultured Bovine Corneal Endothelial Cells
Invest. Ophthalmol. Vis. Sci., January 1, 2005; 46(1): 104 - 113.
[Abstract] [Full Text] [PDF]

Home page
 BloodHome page
H. K. Eltzschig, L. F. Thompson, J. Karhausen, R. J. Cotta, J. C. Ibla, S. C. Robson, and S. P. Colgan
Endogenous adenosine produced during hypoxia attenuates neutrophil accumulation: coordination by extracellular nucleotide metabolism
Blood, December 15, 2004; 104(13): 3986 - 3992.
[Abstract] [Full Text] [PDF]

Home page
 BloodHome page
L. G. Coleman Jr, R. K. Polanowska-Grabowska, M. Marcinkiewicz, and A. R. L. Gear
LDL oxidized by hypochlorous acid causes irreversible platelet aggregation when combined with low levels of ADP, thrombin, epinephrine, or macrophage-derived chemokine (CCL22)
Blood, July 15, 2004; 104(2): 380 - 389.
[Abstract] [Full Text] [PDF]

Home page
 IOVSHome page
T. Chan-Ling, D. S. McLeod, S. Hughes, L. Baxter, Y. Chu, T. Hasegawa, and G. A. Lutty
Astrocyte-Endothelial Cell Relationships during Human Retinal Vascular Development
Invest. Ophthalmol. Vis. Sci., June 1, 2004; 45(6): 2020 - 2032.
[Abstract] [Full Text] [PDF]

Home page
 J. Pharmacol. Exp. Ther.Home page
C. Sesti, M. Koyama, M. J. Broekman, A. J. Marcus, and R. Levi
Ectonucleotidase in Sympathetic Nerve Endings Modulates ATP and Norepinephrine Exocytosis in Myocardial Ischemia
J. Pharmacol. Exp. Ther., July 1, 2003; 306(1): 238 - 244.
[Abstract] [Full Text] [PDF]


Home Help [Feedback] [For Subscribers] [Archive] [Search] [Contents]
All ASPET Journals Molecular Pharmacology Pharmacological Reviews
Molecular Interventions Drug Metabolism and Disposition

Copyright © 2003 by the American Society for Pharmacology and Experimental Therapeutics.