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首页> 外文期刊>Cellular Signalling >FK506 induces endothelial dysfunction through attenuation of Akt and ERK1/2 independently of calcineurin inhibition and the caspase pathway
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FK506 induces endothelial dysfunction through attenuation of Akt and ERK1/2 independently of calcineurin inhibition and the caspase pathway

机译：FK506通过减弱Akt和ERK1 / 2诱导内皮功能障碍，与钙调神经磷酸酶抑制作用和caspase途径无关

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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.
机译：钙调神经磷酸酶抑制剂，例如环孢菌素A（CsA）和FK506已用于实体器官和造血干细胞移植，以抑制免疫功能。但是，这些免疫抑制剂与严重的内皮功能障碍有关。我们使用三维培养血管模型研究了CsA和FK506是否诱导内皮功能障碍，在该模型中，人脐静脉内皮细胞形成并维持了毛细血管和管腔结构。我们发现FK506，而不是CsA，诱导了管结构的破坏和内皮细胞死亡。 FK506抑制钙调神经磷酸酶活性，但FK506诱导的管破裂和细胞死亡不受靶向钙调神经磷酸酶Aα的RNA干扰的抑制。 FK506也诱导胱天蛋白酶激活，但zVAD（OMe）-fmk对胱天蛋白酶的抑制作用不能抑制FK506诱导的管破裂和细胞死亡。 FK506诱导Akt和细胞外调节激酶1/2（ERK1 / 2）的衰减。此外，LY294002的Akt抑制作用或PD98059的ERK1 / 2抑制作用引起管破裂和细胞死亡。目前的结果表明，FK506通过减弱Akt和ERK1 / 2诱导内皮功能障碍，而与钙调神经磷酸酶抑制作用和caspase途径无关。

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