dwyer-ectonucleotide-2012.pdf (856.21 kB)
Ectonucleotide triphosphate diphosphohydrolase-1 (CD39) mediates resistance to occlusive arterial thrombus formation after vascular injury in mice
journal contribution
posted on 2012-07-01, 00:00 authored by Zachary M Huttinger, Michael W Milks, Michael S Nickoli, William L Aurand, Lawrence C Long, Debra G Wheeler, Karen DwyerKaren Dwyer, Anthony J F d'Apice, Simon C Robson, Peter J Cowan, Richard J GuminaModulation of purinergic signaling, which is critical for vascular homeostasis and the response to vascular injury, is regulated by hydrolysis of proinflammatory ATP and/or ADP by ectonucleoside triphosphate diphosphohydrolase 1 (ENTPD-1; CD39) to AMP, which then is hydrolyzed by ecto-5'-nucleotidase (CD73) to adenosine. We report here that compared with littermate controls (wild type), transgenic mice expressing human ENTPDase-1 were resistant to the formation of an occlusive thrombus after FeCl(3)-induced carotid artery injury. Treatment of mice with the nonhydrolyzable ADP analog, adenosine-5'-0-(2-thiodiphosphate) trilithium salt, Ado-5'-PP[S], negated the protection from thrombosis, consistent with a role for ADP in platelet recruitment and thrombus formation. ENTPD-1 expression decreased whole-blood aggregation after stimulation by ADP, an effect negated by adenosine-5'-0-(2-thiodiphosphate) trilithium salt, Ado-5'-PP[S] stimulation, and limited the ability to maintain the platelet fibrinogen receptor, glycoprotein α(IIb)/β(3), in a fully activated state, which is critical for thrombus formation. In vivo treatment with a CD73 antagonist, a nonselective adenosine-receptor antagonist, or a selective A(2A) or A(2B) adenosine-receptor antagonist, negated the resistance to thrombosis in transgenic mice expressing human ENTPD-1, suggesting a role for adenosine generation and engagement of adenosine receptors in conferring in vivo resistance to occlusive thrombosis in this model. In summary, our findings identify ENTPDase-1 modulation of purinergic signaling as a key determinant of the formation of an occlusive thrombus after vascular injury.
History
Journal
American journal of pathologyVolume
181Issue
1Pagination
322 - 333Publisher
ElsevierLocation
Amsterdam, The NetherlandsPublisher DOI
Link to full text
eISSN
1525-2191Language
engPublication classification
C1 Refereed article in a scholarly journalCopyright notice
2012, ElsevierUsage metrics
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AdenosineAnimalsAntigens, CDApyraseCarotid Artery ThrombosisCells, CulturedChloridesFerric CompoundsMiceMice, TransgenicPlatelet ActivationPlatelet AggregationReceptors, Purinergic P2Signal TransductionScience & TechnologyLife Sciences & BiomedicinePathologyINHIBITS PLATELET-AGGREGATIONACUTE CORONARY SYNDROMESTISSUE FACTORADENOSINE-DIPHOSPHATEENDOTHELIAL-CELLSNEUTROPHIL CHEMOTAXISDEPENDENT THROMBOSISTARGETED DISRUPTIONTRANSGENIC MICEHUMAN-BLOOD
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