TY - JOUR
T1 - Ectonucleotide triphosphate diphosphohydrolase-1 (CD39) mediates resistance to occlusive arterial thrombus formation after vascular injury in mice
AU - Huttinger, Zachary M.
AU - Milks, Michael W.
AU - Nickoli, Michael S.
AU - Aurand, William L.
AU - Long, Lawrence C.
AU - Wheeler, Debra G.
AU - Dwyer, Karen M.
AU - D'Apice, Anthony J.F.
AU - Robson, Simon C.
AU - Cowan, Peter J.
AU - Gumina, Richard J.
N1 - Copyright:
Copyright 2012 Elsevier B.V., All rights reserved.
PY - 2012/7
Y1 - 2012/7
N2 - Modulation 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.
AB - Modulation 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.
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U2 - 10.1016/j.ajpath.2012.03.024
DO - 10.1016/j.ajpath.2012.03.024
M3 - Article
C2 - 22613024
AN - SCOPUS:84862697341
VL - 181
SP - 322
EP - 333
JO - American Journal of Pathology
JF - American Journal of Pathology
SN - 0002-9440
IS - 1
ER -