dwyer-roleofthecd39cd73-2016.pdf (2.16 MB)
Role of the CD39/CD73 purinergic pathway in modulating arterial thrombosis in mice
journal contribution
posted on 2016-09-01, 00:00 authored by R Covarrubias, E Chepurko, A Reynolds, Z M Huttinger, R Huttinger, K Stanfill, D G Wheeler, T Novitskaya, S C Robson, Karen DwyerKaren Dwyer, P J Cowan, R J GuminaObjective-Circulating blood cells and endothelial cells express ectonucleoside triphosphate diphosphohydrolase-1 (CD39) and ecto-5'-nucleotidase (CD73). CD39 hydrolyzes extracellular ATP or ADP to AMP. CD73 hydrolyzes AMP to adenosine. The goal of this study was to examine the interplay between CD39 and CD73 cascade in arterial thrombosis. Approach and Results-To determine how CD73 activity influences in vivo thrombosis, the time to ferric chloride-induced arterial thrombosis was measured in CD73-null mice. In response to 5% FeCl3, but not to 10% FeCl3, there was a significant decrease in the time to thrombosis in CD73-null mice compared with wild-Type mice. In mice overexpressing CD39, ablation of CD73 did not inhibit the prolongation in the time to thrombosis conveyed by CD39 overexpression. However, the CD73 inhibitor α-β-methylene-ADP nullified the prolongation in the time to thrombosis in human CD39 transgenic (hC39-Tg)/CD73-null mice. To determine whether hematopoietic-derived cells or endothelial cell CD39 activity regulates in vivo arterial thrombus, bone marrow transplant studies were conducted. FeCl3-induced arterial thrombosis in chimeric mice revealed a significant prolongation in the time to thrombosis in hCD39-Tg reconstituted wild-Type mice, but not on wild-Type reconstituted hCD39-Tg mice. Monocyte depletion with clodronate-loaded liposomes normalized the time to thrombosis in hCD39-Tg mice compared with hCD39-Tg mice treated with control liposomes, demonstrating that increased CD39 expression on monocytes protects against thrombosis. Conclusions-These data demonstrate that ablation of CD73 minimally effects in vivo thrombosis, but increased CD39 expression on hematopoietic-derived cells, especially monocytes, attenuates in vivo arterial thrombosis.
History
Journal
Arteriosclerosis, thrombosis, and vascular biologyVolume
36Issue
9Pagination
1809 - 1820Publisher
Lippincott Williams & WilkinsLocation
Philadelphia, Pa.Publisher DOI
Link to full text
ISSN
1079-5642eISSN
1524-4636Language
engPublication classification
C Journal article; C1 Refereed article in a scholarly journalCopyright notice
2016, American Heart Association, Inc.Usage metrics
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Science & TechnologyLife Sciences & BiomedicineHematologyPeripheral Vascular DiseaseCardiovascular System & Cardiologyadenosine diphosphatemonocytesnucleotidaseplatelet activationthrombosisINDUCED PLATELET-AGGREGATIONMOUSE MODELECTO-5'-NUCLEOTIDASE CD73ADENOSINE-TRIPHOSPHATEALKALINE-PHOSPHATASETARGETED DISRUPTIONENDOTHELIAL-CELLSCD39THROMBOREGULATIONMECHANISMS
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