Thromboregulatory manifestations in human CD39 transgenic mice and the implications for thrombotic disease and transplantation.
Extracellular nucleotides play an important role in thrombosis and inflammation, triggering a range of effects such as platelet activation and recruitment, endothelial cell activation, and vasoconstriction. CD39, the major vascular nucleoside triphosphate diphosphohydrolase (NTPDase), converts ATP and ADP to AMP, which is further degraded to the antithrombotic and anti-inflammatory mediator adenosine. Deletion of CD39 renders mice exquisitely sensitive to vascular injury, and CD39-null cardiac xenografts show reduced survival. Conversely, upregulation of CD39 by somatic gene transfer or administration of soluble NTPDases has major benefits in models of transplantation and inflammation. In this study we examined the consequences of transgenic expression of human CD39 (hCD39) in mice. Importantly, these mice displayed no overt spontaneous bleeding tendency under normal circumstances. The hCD39 transgenic mice did, however, exhibit impaired platelet aggregation, prolonged bleeding times, and resistance to systemic thromboembolism. Donor hearts transgenic for hCD39 were substantially protected from thrombosis and survived longer in a mouse cardiac transplant model of vascular rejection. These thromboregulatory manifestations in hCD39 transgenic mice suggest important therapeutic potential in clinical vascular disease and in the control of serious thrombotic events that compromise the survival of porcine xenografts in primates.
Dwyer
Karen M
KM
Immunology Research Center and Department of Medicine, St. Vincent's Hospital, University of Melbourne, Victoria, Australia.
Robson
Simon C
SC
Nandurkar
Harshal H
HH
Campbell
Duncan J
DJ
Gock
Hilton
H
Murray-Segal
Lisa J
LJ
Fisicaro
Nella
N
Mysore
Tharun B
TB
Kaczmarek
Elzbieta
E
Cowan
Peter J
PJ
d'Apice
Anthony J F
AJ
D000241:Adenosine / Q000097:blood; D000249:Adenosine Monophosphate / Q000097:blood; D000251:Adenosine Triphosphatases / Q000235:genetics* / Q000502:physiology*; D000818:Animals; D015703:Antigens, CD / Q000235:genetics* / Q000502:physiology*; D001081:Apyrase; D001792:Blood Platelets / Q000502:physiology; D016026:Bone Marrow Transplantation / Q000276:immunology; D015870:Gene Expression; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D008822:Mice, Transgenic; D010641:Phenotype; D013927:Thrombosis / Q000235:genetics / Q000276:immunology*; D014181:Transplantation Immunology
D015703:Antigens, CD; D000249:Adenosine Monophosphate; D000251:Adenosine Triphosphatases; D001081:Apyrase; C067869:CD39 antigen; D000241:Adenosine