Wei Li1, Alba Gigante2, Maria-Jesus Perez-Perez2, Hong Yue2, Michio Hirano2, Thomas M McIntyre2, Roy L Silverstein2. 1. From the Department of Cellular and Molecular Medicine, Lerner Research Institute, The Cleveland Clinic, OH (W.L., T.M.M.); Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, OH (W.L., T.M.M.); Instituto de Quimica Medica, Consejo Superior De Investigaciones Cientificas (IQM-CSIC), Madrid, Spain (A.G.,M.-J.P.-P.); Department of Biological Sciences, Case Western Reserve University, Cleveland, OH (H.Y.); Department of Neurology, Columbia University Medical Center, New York, NY (M.H.); and Department of Medicine, Medical College of Wisconsin and Blood Research Institute, Blood Center of Wisconsin, Milwaukee (R.L.S.) liw4@ccf.org. 2. From the Department of Cellular and Molecular Medicine, Lerner Research Institute, The Cleveland Clinic, OH (W.L., T.M.M.); Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, OH (W.L., T.M.M.); Instituto de Quimica Medica, Consejo Superior De Investigaciones Cientificas (IQM-CSIC), Madrid, Spain (A.G.,M.-J.P.-P.); Department of Biological Sciences, Case Western Reserve University, Cleveland, OH (H.Y.); Department of Neurology, Columbia University Medical Center, New York, NY (M.H.); and Department of Medicine, Medical College of Wisconsin and Blood Research Institute, Blood Center of Wisconsin, Milwaukee (R.L.S.).
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.
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 1tyrosine 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.
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