期刊
AMERICAN JOURNAL OF PATHOLOGY
卷 181, 期 1, 页码 322-333出版社
ELSEVIER SCIENCE INC
DOI: 10.1016/j.ajpath.2012.03.024
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资金
- NIH, National Heart, Lung, and Blood Institute [HL094703, HL096038]
- American Heart Association-Great Rivers Affiliate Student Undergraduate Research Fellowship [10UFEL4180090]
- Davis Heart and Lung Research Institute
- Academic Advisory Committee
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 FeCl3-induced carotid artery injury. Treatment of mice with the nonhydrolyzable ADP analog, adenosine-5'-O-(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'-O-(2-thiodiphosphate) trilithium salt, Ado-5'-PP[S] stimulation, and limited the ability to maintain the platelet fibrinogen receptor, glycoprotein alpha(IIb)/beta(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 or A 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. (Am J Pathol 2012, 181:322-333; http://dx.doi.org/10.1016/j.ajpath.2012.03.024)
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