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Thymidine phosphorylase participates in platelet signaling and promotes thrombosis

AuthorsLi, Wei; Gigante, Alba ; Peréz-Pérez, María-Jesús ; Yue, H.; Hirano, Michio; McIntyre, T. M.; Silverstein, R. L.
Issue Date2014
PublisherLippincott Williams & Wilkins
CitationCirculation Research 115: 997-1006 (2014)
AbstractRationale: Platelets contain abundant thymidine phosphorylase (TYMP), which is highly expressed in diseases with high risk of thrombosis, such as atherosclerosis and type II diabetes mellitus. Objective: To test the hypothesis that TYMP participates in platelet signaling and promotes thrombosis. Methods and Results: By using a ferric chloride (FeCl3)induced carotid artery injury thrombosis model, we found time to blood flow cessation was significantly prolonged in Tymp?/? and Tymp+/? mice compared with wildtype mice. Bone marrow transplantation and platelet transfusion studies demonstrated that platelet TYMP was responsible for the antithrombotic phenomenon in the TYMP-deficient mice. Collagen-, collagen-related peptide, adenosine diphosphate-, or thrombin-induced platelet aggregation were significantly attenuated in Tymp+/? and Tymp?/? platelets, and in wild type or human platelets pretreated with TYMP inhibitor KIN59. Tymp deficiency also significantly decreased agonist-induced P-selectin expression. TYMP contains an N-terminal SH3 domainbinding proline-rich motif and forms a complex with the tyrosine kinases Lyn, Fyn, and Yes in platelets. TYMPassociated Lyn was inactive in resting platelets, and TYMP trapped and diminished active Lyn after collagen stimulation. Tymp/Lyn double haploinsufficiency diminished the antithrombotic phenotype of Tymp+/? mice. TYMP deletion or inhibition of TYMP with KIN59 dramatically increased platelet-endothelial cell adhesion molecule 1 tyrosine phosphorylation and diminished collagen-related peptide or collagen-induced AKT phosphorylation. In vivo administration of KIN59 significantly inhibited FeCl3-induced carotid artery thrombosis without affecting hemostasis. Conclusions: TYMP participates in multiple platelet signaling pathways and regulates platelet activation and thrombosis. Targeting TYMP might be a novel antiplatelet and antithrombosis therapy.
DOIhttp://dx.doi.org/10.1161/CIRCRESAHA. 115.304591
Identifiersdoi: 10.1161/CIRCRESAHA. 115.304591
issn: 0009-7330
e-issn: 1524-4571
Appears in Collections:(IQM) Artículos
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