Elucidation of the thromboregulatory role of CD39/ectoapyrase in the ischemic brain

David J. Pinsky, M. Johan Broekman, Jacques J. Peschon, Kim L. Stocking, Tomoyuki Fujita, Ravichandran Ramasamy, E. Sander Connolly, Judy Huang, Szilard Kiss, Yuan Zhang, Tanvir F. Choudhri, Ryan A. McTaggart, Hui Liao, Joan H F Drosopoulos, Virginia L. Price, Aaron J. Marcus, Charles R. Maliszewski

Research output: Contribution to journalArticle

Abstract

Endothelial CD39 metabolizes ADP released from activated platelets. Recombinant soluble human CD39 (solCD39) potently inhibited ex vivo platelet aggregation in response to ADP and reduced cerebral infarct volumes in mice following transient middle cerebral artery occlusion, even when given 3 hours after stroke. Postischemic platelet and fibrin deposition were decreased and perfusion increased without increasing intracerebral hemorrhage. In contrast, aspirin did not increase postischemic blood flow or reduce infarction volume, but did increase intracerebral hemorrhage. Mice lacking the enzymatically active extracellular portion of the CD39 molecule were generated by replacement of exons 4-6 (apyrase-conserved regions 2-4) with a PGKneo cassette. Although CD39 mRNA 3′ of the neomycin cassette insertion site was detected, brains from these mice lacked both apyrase activity and CD39 immunoreactivity. Although their baseline phenotype, hematological profiles, and bleeding times were normal, cd39-/- mice exhibited increased cerebral infarct volumes and reduced postischemic perfusion. solCD39 reconstituted these mice, restoring postischemic cerebral perfusion and rescuing them from cerebral injury. These data demonstrate that CD39 exerts a protective thromboregulatory function in stroke.

Original languageEnglish (US)
Pages (from-to)1031-1040
Number of pages10
JournalJournal of Clinical Investigation
Volume109
Issue number8
DOIs
StatePublished - 2002
Externally publishedYes

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Apyrase
Brain
Perfusion
Cerebral Hemorrhage
Adenosine Diphosphate
Blood Platelets
Stroke
Bleeding Time
Neomycin
Middle Cerebral Artery Infarction
Fibrin
Platelet Aggregation
Infarction
Aspirin
Exons
CD39 antigen
Phenotype
Messenger RNA
Wounds and Injuries

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Pinsky, D. J., Johan Broekman, M., Peschon, J. J., Stocking, K. L., Fujita, T., Ramasamy, R., ... Maliszewski, C. R. (2002). Elucidation of the thromboregulatory role of CD39/ectoapyrase in the ischemic brain. Journal of Clinical Investigation, 109(8), 1031-1040. https://doi.org/10.1172/JCI200210649

Elucidation of the thromboregulatory role of CD39/ectoapyrase in the ischemic brain. / Pinsky, David J.; Johan Broekman, M.; Peschon, Jacques J.; Stocking, Kim L.; Fujita, Tomoyuki; Ramasamy, Ravichandran; Sander Connolly, E.; Huang, Judy; Kiss, Szilard; Zhang, Yuan; Choudhri, Tanvir F.; McTaggart, Ryan A.; Liao, Hui; Drosopoulos, Joan H F; Price, Virginia L.; Marcus, Aaron J.; Maliszewski, Charles R.

In: Journal of Clinical Investigation, Vol. 109, No. 8, 2002, p. 1031-1040.

Research output: Contribution to journalArticle

Pinsky, DJ, Johan Broekman, M, Peschon, JJ, Stocking, KL, Fujita, T, Ramasamy, R, Sander Connolly, E, Huang, J, Kiss, S, Zhang, Y, Choudhri, TF, McTaggart, RA, Liao, H, Drosopoulos, JHF, Price, VL, Marcus, AJ & Maliszewski, CR 2002, 'Elucidation of the thromboregulatory role of CD39/ectoapyrase in the ischemic brain', Journal of Clinical Investigation, vol. 109, no. 8, pp. 1031-1040. https://doi.org/10.1172/JCI200210649
Pinsky DJ, Johan Broekman M, Peschon JJ, Stocking KL, Fujita T, Ramasamy R et al. Elucidation of the thromboregulatory role of CD39/ectoapyrase in the ischemic brain. Journal of Clinical Investigation. 2002;109(8):1031-1040. https://doi.org/10.1172/JCI200210649
Pinsky, David J. ; Johan Broekman, M. ; Peschon, Jacques J. ; Stocking, Kim L. ; Fujita, Tomoyuki ; Ramasamy, Ravichandran ; Sander Connolly, E. ; Huang, Judy ; Kiss, Szilard ; Zhang, Yuan ; Choudhri, Tanvir F. ; McTaggart, Ryan A. ; Liao, Hui ; Drosopoulos, Joan H F ; Price, Virginia L. ; Marcus, Aaron J. ; Maliszewski, Charles R. / Elucidation of the thromboregulatory role of CD39/ectoapyrase in the ischemic brain. In: Journal of Clinical Investigation. 2002 ; Vol. 109, No. 8. pp. 1031-1040.
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