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- Title
Thromboregulatory manifestations in human CD39 transgenic mice and the implications for thrombotic disease and transplantation.
- Authors
Dwyer, Karen M.; Robson, Simon C.; Nandurkar, Harshal H.; Campbell, Duncan J.; Gock, Hilton; Murray-Segal, Lisa J.; Fisicaro, Nella; Mysore, Tharun B.; Kaczmarek, Elzbieta; Cowan, Peter J.; D'Apicel, Anthony J. F
- Abstract
Extracellular nucleotides play an important role in thrombosis and inf lammation,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-inf lammatory 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 inf lammation.In this study we examined the conse- quences 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 thromboembo- lism.Donor hearts transgenic for hCD39 were substantially protected from thrombosis and survived lon- ger 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.
- Subjects
THROMBOSIS; CARDIOVASCULAR diseases; TRANSPLANTATION of organs, tissues, etc.; TRANSGENIC mice; NUCLEOTIDES; BLOOD platelet aggregation
- Publication
Journal of Clinical Investigation, 2004, Vol 113, Issue 10, p1440
- ISSN
0021-9738
- Publication type
Article
- DOI
10.1172/JCI200419560