title: FK506 induces endothelial dysfunction through attenuation of Akt and ERK1/2 independently of calcineurin inhibition and the caspase pathway.
abstract: Calcineurin inhibitors such as cyclosporin A (CsA) and FK506 have been used in solid organ and hematopoietic stem cell transplantations to suppress immune function. However, these immunosuppresants are associated with severe endothelial dysfunction. We investigated whether CsA and FK506 induce endothelial dysfunction using a three-dimensional culture blood vessel model, in which human umbilical vein endothelial cells form and maintain capillary-like tube and lumen structures. We found that FK506, but not CsA, induced breakdown of the tube structures and endothelial cell death. FK506 inhibited calcineurin activity, but FK506-induced tube breakdown and cell death was not suppressed by RNA interference targeting calcineurin Aα. FK506 also induced caspase activation, but caspase inhibition by zVAD(OMe)-fmk failed to suppress FK506-induced tube breakdown and cell death. FK506 induced attenuation of Akt and extracellular-regulated kinase 1/2 (ERK1/2). Furthermore, Akt inhibition by LY294002 or ERK1/2 inhibition by PD98059 induced tube breakdown and cell death. Present results suggest that FK506 induces endothelial dysfunction through attenuation of Akt and ERK1/2 independently of calcineurin inhibition and the caspase pathway.
authors.affiliation: Division of Hematology, Department of Internal Medicine, Laboratory of Cell Transplantation, Institute for Advanced Medical Sciences, Hyogo College of Medicine, Nishinomiya, Japan. r-eguchi@hyo-med.ac.jp
authors.forename: Ryoji
authors.initials: R
authors.lastname: Eguchi
authors.forename: Shuji
authors.initials: S
authors.lastname: Kubo
authors.forename: Toshiro
authors.initials: T
authors.lastname: Ohta
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Kunimasa
authors.forename: Masaya
authors.initials: M
authors.lastname: Okada
authors.forename: Hiroya
authors.initials: H
authors.lastname: Tamaki
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Kaji
authors.forename: Ichiro
authors.initials: I
authors.lastname: Wakabayashi
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Fujimori
authors.forename: Hiroyasu
authors.initials: H
authors.lastname: Ogawa
mesh_terms: D019703:Calcineurin / Q000378:metabolism; D065095:Calcineurin Inhibitors; D020169:Caspases / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D016572:Cyclosporine / Q000494:pharmacology; D042783:Endothelial Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D016559:Tacrolimus / Q000494:pharmacology*
chemical_list: D065095:Calcineurin Inhibitors; D004791:Enzyme Inhibitors; D007166:Immunosuppressive Agents; D016572:Cyclosporine; D051057:Proto-Oncogene Proteins c-akt; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D019703:Calcineurin; D020169:Caspases; D016559:Tacrolimus