title: Recombinant human soluble thrombomodulin attenuates FK506-induced endothelial dysfunction through prevention of Akt inactivation.
abstract: Thrombomodulin (TM), a transmembrane glycoprotein on vascular endothelial cells, is a naturally occurring anticoagulant. Recombinant human soluble TM (rTM), composed of the extracellular domain of TM, also shows anti-coagulant and anti-inflammatory activity, but the effects of rTM on microangiopathy remain unclear. We reported that FK506 induced endothelial dysfunction through inactivation of Akt and extracellular-regulated kinase 1/2 using a three-dimensional culture blood vessel model. In the present study, we examined the effects of rTM on FK506-induced endothelial dysfunction. We found that rTM suppressed FK506-induced endothelial cell death, but not the breakdown of capillary-like tube structures. rTM prevented FK506-induced inactivation of Akt, but not of extracellular-regulated kinase 1/2. Akt inhibition by LY294002 abrogated the preventive effect of rTM on FK506-induced Akt inactivation and the suppressive effect of rTM on FK506-induced cell death. These results suggest that rTM attenuates FK506-induced endothelial dysfunction through prevention of Akt inactivation.
authors.affiliation: Division of Hematology, Department of Internal Medicine, Laboratory of Cell Transplantation, Institute for Advanced Medical Sciences, Hyogo College of Medicine, Nishinomiya, Japan; Department of Environmental and Preventive Medicine, Hyogo College of Medicine, Nishinomiya, Japan. Electronic address: r-eguchi@hyo-med.ac.jp.
authors.forename: Ryoji
authors.initials: R
authors.lastname: Eguchi
authors.affiliation: Division of Hematology, Department of Internal Medicine, Laboratory of Cell Transplantation, Institute for Advanced Medical Sciences, Hyogo College of Medicine, Nishinomiya, Japan. Electronic address: fuji-y@hyo-med.ac.jp.
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Fujimori
authors.affiliation: Division of Hematology, Department of Internal Medicine, Laboratory of Cell Transplantation, Institute for Advanced Medical Sciences, Hyogo College of Medicine, Nishinomiya, Japan.
authors.forename: Masaya
authors.initials: M
authors.lastname: Okada
authors.affiliation: Division of Hematology, Department of Internal Medicine, Laboratory of Cell Transplantation, Institute for Advanced Medical Sciences, Hyogo College of Medicine, Nishinomiya, Japan.
authors.forename: Hiroya
authors.initials: H
authors.lastname: Tamaki
authors.affiliation: Department of Environmental and Preventive Medicine, Hyogo College of Medicine, Nishinomiya, Japan.
authors.forename: Ichiro
authors.initials: I
authors.lastname: Wakabayashi
authors.affiliation: Division of Hematology, Department of Internal Medicine, Laboratory of Cell Transplantation, Institute for Advanced Medical Sciences, Hyogo College of Medicine, Nishinomiya, Japan.
authors.forename: Hiroyasu
authors.initials: H
authors.lastname: Ogawa
mesh_terms: D016923:Cell Death / Q000187:drug effects; D002460:Cell Line; D002867:Chromones / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D016222:Fibroblast Growth Factor 2 / Q000378:metabolism; D024243:HMGB1 Protein / Q000378:metabolism; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects* / Q000378:metabolism*; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology; D009025:Morpholines / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011994:Recombinant Proteins / Q000494:pharmacology*; D016559:Tacrolimus / Q000494:pharmacology*; D018180:Thrombomodulin; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
chemical_list: D002867:Chromones; D004791:Enzyme Inhibitors; D024243:HMGB1 Protein; C585491:HMGB1 protein, human; D007166:Immunosuppressive Agents; D009025:Morpholines; D011994:Recombinant Proteins; D018180:Thrombomodulin; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D016222:Fibroblast Growth Factor 2; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; D051057:Proto-Oncogene Proteins c-akt; D016559:Tacrolimus
keywords: Akt; ERK1/2; Endothelial dysfunction; FK506; HMGB1; rTM