Faculty Collaboration Database

Thymidine phosphorylase participates in platelet signaling and promotes thrombosis. Circ Res 2014 Dec 05;115(12):997-1006

Date

10/08/2014

Pubmed ID

25287063

Pubmed Central ID

PMC4258140

DOI

10.1161/CIRCRESAHA.115.304591

Scopus ID

2-s2.0-84917682250 (requires institutional sign-in at Scopus site)   32 Citations

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.

Author List

Li W, Gigante A, Perez-Perez MJ, Yue H, Hirano M, McIntyre TM, Silverstein RL

Author

Roy L. Silverstein MD Professor in the Medicine department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Amino Acid Sequence
Animals
Blood Platelets
Bone Marrow Transplantation
Chlorides
Enzyme Inhibitors
Ferric Compounds
Haploinsufficiency
Humans
Male
Mice, Inbred C57BL
Mice, Knockout
Molecular Sequence Data
Phenotype
Phosphorylation
Platelet Aggregation
Platelet Aggregation Inhibitors
Platelet Transfusion
Proto-Oncogene Proteins c-akt
Proto-Oncogene Proteins c-fyn
Proto-Oncogene Proteins c-yes
Selenoprotein P
Signal Transduction
Thrombosis
Thymidine Phosphorylase
Time Factors
src-Family Kinases