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Thymidine phosphorylase participates in platelet signaling and promotes thrombosis.


ABSTRACT:

Rationale

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 wild-type 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 domain-binding proline-rich motif and forms a complex with the tyrosine kinases Lyn, Fyn, and Yes in platelets. TYMP-associated 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.

SUBMITTER: Li W 

PROVIDER: S-EPMC4258140 | biostudies-literature | 2014 Dec

REPOSITORIES: biostudies-literature

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Publications

Thymidine phosphorylase participates in platelet signaling and promotes thrombosis.

Li Wei W   Gigante Alba A   Perez-Perez Maria-Jesus MJ   Yue Hong H   Hirano Michio M   McIntyre Thomas M TM   Silverstein Roy L RL  

Circulation research 20141006 12


<h4>Rationale</h4>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.<h4>Objective</h4>To test the hypothesis that TYMP participates in platelet signaling and promotes thrombosis.<h4>Methods and results</h4>By using a ferric chloride (FeCl3)-induced carotid artery injury thrombosis model, we found time to blood flow cessation was significantly prolonged in Tymp(-/-) a  ...[more]

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