| Autor: |
Jácomo RH; National Institute of Science and Technology in Stem Cell and Cell Therapy, Division of Oncology/Hematology, Department of Internal Medicine, Medical School of Ribeirão Preto, University of São Paulo, São Paulo, Brazil., Santana-Lemos BA, Lima AS, Assis PA, Lange AP, Figueiredo-Pontes LL, Oliveira LO, Bassi SC, Benício MT, Baggio MS, Garcia AB, Falcão RP, Rego EM |
| Jazyk: |
angličtina |
| Zdroj: |
Blood [Blood] 2012 Jul 05; Vol. 120 (1), pp. 207-13. Date of Electronic Publication: 2012 Apr 19. |
| DOI: |
10.1182/blood-2011-04-347187 |
| Abstrakt: |
Increased fibrinolysis is an important component of acute promyelocytic leukemia (APL) bleeding diathesis. APL blasts overexpress annexin II (ANXII), a receptor for tissue plasminogen activator (tPA), and plasminogen, thereby increasing plasmin generation. Previous studies suggested that ANXII plays a pivotal role in APL coagulopathy. ANXII binding to tPA can be inhibited by homocysteine and hyperhomocysteinemia can be induced by L-methionine supplementation. In the present study, we used an APL mouse model to study ANXII function and the effects of hyperhomocysteinemia in vivo. Leukemic cells expressed higher ANXII and tPA plasma levels (11.95 ng/mL in leukemic vs 10.74 ng/mL in wild-type; P = .004). In leukemic mice, administration of L-methionine significantly increased homocysteine levels (49.0 μmol/mL and < 6.0 μmol/mL in the treated and nontreated groups, respectively) and reduced tPA levels to baseline concentrations. The latter were also decreased after infusion of the LCKLSL peptide, a competitor for the ANXII tPA-binding site (11.07 ng/mL; P = .001). We also expressed and purified the p36 component of ANXII in Pichia methanolica. The infusion of p36 in wild-type mice increased tPA and thrombin-antithrombin levels, and the latter was reversed by L-methionine administration. The results of the present study demonstrate the relevance of ANXII in vivo and suggest that methionine-induced hyperhomocysteinemia may reverse hyperfibrinolysis in APL. |
| Databáze: |
MEDLINE |
| Externí odkaz: |
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