Thrombomodulin Protects Endothelial Cells From a Calcineurin Inhibitor-Induced Cytotoxicity by Upregulation of Extracellular Signal-Regulated Kinase/Myeloid Leukemia Cell-1 Signaling

被引:54
作者
Ikezoe, Takayuki [1 ]
Yang, Jing [1 ]
Nishioka, Chie [1 ,3 ]
Honda, Goichi [4 ]
Furihata, Mutsuo [2 ]
Yokoyama, Akihito [1 ]
机构
[1] Kochi Univ, Dept Hematol & Resp Med, Nanko Ku, Kochi 7838505, Japan
[2] Kochi Univ, Dept Pathol, Nanko Ku, Kochi 7838505, Japan
[3] Japan Soc Promot Sci, Chiyoda Ku, Tokyo, Japan
[4] Asahi Kasei Pharma, ART Project, Chiyoda Ku, Tokyo, Japan
关键词
vascular biology; extracellular signal-regulated kinase; myeloid leukemia cell-1; endothelial cells; thrombomodulin; LECTIN-LIKE DOMAIN; HUMAN SOLUBLE THROMBOMODULIN; LEWIS Y ANTIGEN; FACTOR-KAPPA-B; COFACTOR ACTIVITY; GROWTH ARREST; CANCER CELLS; C PATHWAY; ANTICOAGULANT; ACTIVATION;
D O I
10.1161/ATVBAHA.112.251157
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
Objective-We have recently reported that recombinant human soluble thrombomodulin (rTM) counteracted capillary leakage associated with engraftment, as well as sinusoidal obstructive syndrome after hematopoietic stem cell transplantation. These observations prompted us to explore whether rTM possessed cytoprotective effects on endothelial cells. Methods and Results-Exposure of human umbilical vein endothelial cells to rTM induced expression of antiapoptotic protein myeloid leukemia cell-1 through the activation of extracellular signal-regulated kinase in these cells. Additional studies found that exposure of human umbilical vein endothelial cells to cyclosporine A and FK506, an immunosuppressant used for the individuals receiving hematopoietic stem cell transplantation, induced apoptosis, which was attenuated when human umbilical vein endothelial cells were exposed to these agents in the presence of rTM. Further studies using deletion mutants of thrombomodulin (TM) identified that the epidermal growth factor domain of TM possessed cytoprotective effects. A single nucleotide substitution at codon 376 or 424 of TM, which impairs the ability of TM to produce activated protein C or bind to thrombin, respectively, did not hamper the cytoprotective effects of TM, which suggested that cytoprotective effects of rTM were distinctive from those of activated protein C. Conclusion-TM may be useful for prevention, as well as treatment of endothelial cell damage after hematopoietic stem cell transplantation. (Arterioscler Thromb Vasc Biol. 2012;32:2259-2270.)
引用
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页码:2259 / +
页数:16
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