Abstract 18147: Role of Adenosine Receptor Engagement in Ectonucleotide Triphosphate Diphosphohydrolase-1 Mediated Resistance to Conduit Arterial Thrombosis in Mice
Background: Ectonucleoside Triphosphate Diphosphohydrolase-1 (ENTPD-1/CD39) plays a key role in regulating platelet reactivity; it converts prothrombotic ATP and ADP to AMP which is further degraded by ecto-5’-nucleotidase (CD73) to adenosine, an anti-thrombotic mediator. The objective was to determine role of adenosine receptor engagement in ENTPDase-1 mediated resistance to in vivo arterial thrombosis in mice.
Methods: Transgenic mice expressing human ENTPD-1 and littermate controls (WT) were subjected to FeCl3-induced carotid artery thrombosis.
Results: ENTPD-1 mice displayed marked resistance to thrombosis (WT: 13.7 ± 0.9 min vs. ENTPD-1: 281.5 ± 57.3 min; P<0.001; n=6/group; Figure). Treatment of mice with α-β-methylene-ADP (APCP; 2 mg/kg 15 minute prior to injury), a specific ecto-5’-nucleotidase antagonist, completely abrogated the protection from thrombosis mediated by ENTPD-1 overexpression (APCP-treated WT: 11.9 ± 1.0min vs. APCP-treated ENTPD-1: 26.5 ± 11.1 min; n=6/group; Figure), suggesting that ecto-5’-nucleotidase-mediated generation of adenosine is required for ENTPD-1 mediated resistance to in vivo thrombosis. Furthermore, in mice treated with the non-selective adenosine receptor antagonist 8-(p-Sulfophenyl) theophylline (8-SPT; 20 mg /kg 15 minutes prior to injury) the resistance to thrombosis observed in ENTPDase-1 overexpresssing mice was abrogated (8-SPT Treated WT (n=8): 10.5 ± 1.4 min vs. 8-SPT Treated ENTPD-1 (n=9): 14.3 ± 1.6 min; Figure).
Conclusions: Adenosine receptor engagement contributes to the resistance to thrombosis mediated by ENTPDase-1 overexpression.
- © 2011 by American Heart Association, Inc.