FK506 induces endothelial dysfunction through attenuation of Akt and ERK1/2 independently of calcineurin inhibition and the caspase pathway
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- 作者：Ryoji Eguchi ; Shuji Kubo ; Toshiro Ohta ; Kazuhiro Kunimasa ; Masaya Okada ; Hiroya Tamaki ; Kazuhiko Kaji ; Ichiro Wakabayashi ; Yoshihiro Fujimori ; Hiroyasu Ogawa
- 关键词：ANOVA ; analysis of variance ; bFGF ; basic fibroblast growth factor ; CsA ; cyclosporin A ; DMSO ; dimethylsulfoxide ; EGF ; epidermal growth factor ; eNOS ; endothelial nitrogen oxide synthase ; ERK ; extracellular-regulated kinase ; FKBP ; FK506-binding protein ; GAPD
- 刊名：Cellular Signalling
- 出版年：2013
- 出版时间：September, 2013
- 年：2013
- 卷：25
- 期：9
- 页码：1731-1738
- 全文大小：1342 K
文摘
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 A¦Á. 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.