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
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机构:
Kochi Univ, Dept Hematol & Resp Med, Nanko Ku, Kochi 7838505, JapanKochi Univ, Dept Hematol & Resp Med, Nanko Ku, Kochi 7838505, Japan
Ikezoe, Takayuki
[1
]
Yang, Jing
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机构:
Kochi Univ, Dept Hematol & Resp Med, Nanko Ku, Kochi 7838505, JapanKochi Univ, Dept Hematol & Resp Med, Nanko Ku, Kochi 7838505, Japan
Yang, Jing
[1
]
Nishioka, Chie
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机构:
Kochi Univ, Dept Hematol & Resp Med, Nanko Ku, Kochi 7838505, Japan
Japan Soc Promot Sci, Chiyoda Ku, Tokyo, JapanKochi Univ, Dept Hematol & Resp Med, Nanko Ku, Kochi 7838505, Japan
Nishioka, Chie
[1
,3
]
Honda, Goichi
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机构:
Asahi Kasei Pharma, ART Project, Chiyoda Ku, Tokyo, JapanKochi Univ, Dept Hematol & Resp Med, Nanko Ku, Kochi 7838505, Japan
Honda, Goichi
[4
]
Furihata, Mutsuo
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Kochi Univ, Dept Pathol, Nanko Ku, Kochi 7838505, JapanKochi Univ, Dept Hematol & Resp Med, Nanko Ku, Kochi 7838505, Japan
Furihata, Mutsuo
[2
]
Yokoyama, Akihito
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Kochi Univ, Dept Hematol & Resp Med, Nanko Ku, Kochi 7838505, JapanKochi Univ, Dept Hematol & Resp Med, Nanko Ku, Kochi 7838505, Japan
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
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.)
机构:
Univ Massachusetts, Sch Med, Howard Hughes Med Inst, Program Mol Med,Dept Biochem & Mol Biol, Worcester, MA 01605 USAUniv Massachusetts, Sch Med, Howard Hughes Med Inst, Program Mol Med,Dept Biochem & Mol Biol, Worcester, MA 01605 USA
机构:
Univ Calif Los Angeles, Sch Med, Cedars Sinai Res Inst, Div Hematol Oncol, Los Angeles, CA 90048 USAUniv Calif Los Angeles, Sch Med, Cedars Sinai Res Inst, Div Hematol Oncol, Los Angeles, CA 90048 USA
Ikezoe, T
;
Yang, Y
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机构:Univ Calif Los Angeles, Sch Med, Cedars Sinai Res Inst, Div Hematol Oncol, Los Angeles, CA 90048 USA
Yang, Y
;
Taguchi, H
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机构:Univ Calif Los Angeles, Sch Med, Cedars Sinai Res Inst, Div Hematol Oncol, Los Angeles, CA 90048 USA
Taguchi, H
;
Koeffler, HP
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机构:Univ Calif Los Angeles, Sch Med, Cedars Sinai Res Inst, Div Hematol Oncol, Los Angeles, CA 90048 USA
机构:
Univ Massachusetts, Sch Med, Howard Hughes Med Inst, Program Mol Med,Dept Biochem & Mol Biol, Worcester, MA 01605 USAUniv Massachusetts, Sch Med, Howard Hughes Med Inst, Program Mol Med,Dept Biochem & Mol Biol, Worcester, MA 01605 USA
机构:
Univ Calif Los Angeles, Sch Med, Cedars Sinai Res Inst, Div Hematol Oncol, Los Angeles, CA 90048 USAUniv Calif Los Angeles, Sch Med, Cedars Sinai Res Inst, Div Hematol Oncol, Los Angeles, CA 90048 USA
Ikezoe, T
;
Yang, Y
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h-index: 0
机构:Univ Calif Los Angeles, Sch Med, Cedars Sinai Res Inst, Div Hematol Oncol, Los Angeles, CA 90048 USA
Yang, Y
;
Taguchi, H
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h-index: 0
机构:Univ Calif Los Angeles, Sch Med, Cedars Sinai Res Inst, Div Hematol Oncol, Los Angeles, CA 90048 USA
Taguchi, H
;
Koeffler, HP
论文数: 0引用数: 0
h-index: 0
机构:Univ Calif Los Angeles, Sch Med, Cedars Sinai Res Inst, Div Hematol Oncol, Los Angeles, CA 90048 USA