Elucidation of the thromboregulatory role of CD39/ectoapyrase in the ischemic brain.
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.
Pinsky
David J
DJ
Division of Cardiology, Department of Medicine, College of Physicians and Surgeons, Columbia University, Presbyterial Hospital 10 Stem, 630 W 168th Street, New York, NY 10032, USA. djp5@columbia.edu
Broekman
M Johan
MJ
Peschon
Jacques J
JJ
Stocking
Kim L
KL
Fujita
Tomoyuki
T
Ramasamy
Ravichandran
R
Connolly
E Sander
ES
Huang
Judy
J
Kiss
Szilard
S
Zhang
Yuan
Y
Choudhri
Tanvir F
TF
McTaggart
Ryan A
RA
Liao
Hui
H
Drosopoulos
Joan H F
JH
Price
Virginia L
VL
Marcus
Aaron J
AJ
Maliszewski
Charles R
CR
D000251:Adenosine Triphosphatases / Q000172:deficiency / Q000235:genetics / Q000494:pharmacology / Q000502:physiology*; D000818:Animals; D015703:Antigens, CD / Q000235:genetics / Q000494:pharmacology / Q000502:physiology*; D001081:Apyrase / Q000172:deficiency / Q000235:genetics / Q000494:pharmacology / Q000502:physiology*; D001241:Aspirin / Q000494:pharmacology; D002545:Brain Ischemia / Q000097:blood* / Q000503:physiopathology; D004195:Disease Models, Animal; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010974:Platelet Aggregation / Q000187:drug effects; D020521:Stroke / Q000097:blood / Q000503:physiopathology / Q000517:prevention & control; D013927:Thrombosis / Q000097:blood / Q000503:physiopathology / Q000517:prevention & control
D015703:Antigens, CD; D000251:Adenosine Triphosphatases; D001081:Apyrase; C067869:CD39 antigen; D001241:Aspirin