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http://hdl.handle.net/10261/111660
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dc.contributor.author | Li, Wei | - |
dc.contributor.author | Gigante, Alba | - |
dc.contributor.author | Peréz-Pérez, María-Jesús | - |
dc.contributor.author | Yue, H. | - |
dc.contributor.author | Hirano, Michio | - |
dc.contributor.author | McIntyre, T. M. | - |
dc.contributor.author | Silverstein, R. L. | - |
dc.date.accessioned | 2015-03-03T09:49:48Z | - |
dc.date.available | 2015-03-03T09:49:48Z | - |
dc.date.issued | 2014 | - |
dc.identifier | doi: 10.1161/CIRCRESAHA. 115.304591 | - |
dc.identifier | issn: 0009-7330 | - |
dc.identifier | e-issn: 1524-4571 | - |
dc.identifier.citation | Circulation Research 115: 997-1006 (2014) | - |
dc.identifier.uri | http://hdl.handle.net/10261/111660 | - |
dc.description.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 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. | - |
dc.description.sponsorship | This study was supported by NIH grants HL81011 and HL092747 (to R.L.S.) and AA017748 (to T.M.) and grants of the Spanish CICYT (SAF2009-13914-C02-01 and SAF2012-39760-C02-01). A. G. has a JAE-predoctoral fellowship financed by the CSIC and the FSE (Fondo Social Europeo). | - |
dc.publisher | Lippincott Williams & Wilkins | - |
dc.rights | closedAccess | - |
dc.title | Thymidine phosphorylase participates in platelet signaling and promotes thrombosis | - |
dc.type | artículo | - |
dc.identifier.doi | 10.1161/CIRCRESAHA. 115.304591 | - |
dc.date.updated | 2015-03-03T09:52:14Z | - |
dc.description.version | Peer Reviewed | - |
dc.language.rfc3066 | eng | - |
dc.type.coar | http://purl.org/coar/resource_type/c_6501 | es_ES |
item.fulltext | No Fulltext | - |
item.openairecristype | http://purl.org/coar/resource_type/c_18cf | - |
item.openairetype | artículo | - |
item.cerifentitytype | Publications | - |
item.grantfulltext | none | - |
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