Cyclosporine A--protection against microvascular hyperpermeability is calcineurin independent.
Cyclosporine A--protection against microvascular hyperpermeability is calcineurin independent.
复制标题
环孢素 A——针对微血管通透性过高的保护作用与钙调神经磷酸酶无关。
DOI：
10.1016/j.amjsurg.2009.11.002
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发表时间：
2010
影响因子：
3
通讯作者：
Smythe,WRoy
中科院分区：
文献类型：
--
作者：
Childs,EdW;Tharakan,Binu;Nurudeen,Suliat;Delmas,ThomasL;Hellman,Joseph;Christie,Tasheika;Hunter,FeliciaA;Smythe,WRoy
线粒体介导的凋亡信号参与微血管高通透性。我们假设保护线粒体过渡孔的环孢素A （CsA）可以独立于钙调磷酸酶抑制特性减弱超通透性。方法采用促凋亡BAK或活性caspase-3或钙调磷酸酶自抑制肽（CIP）处理诱导微血管内皮细胞单层高通透性。通透性是根据fitc -白蛋白在单层上的通量来测量的。JC-1检测线粒体跨膜电位（MTP）。采用ELISA法和caspase-3荧光法测定线粒体细胞色素c的释放。结果CsA （10 nM）可减弱bac诱导的高通透性（p < 0.05），而CIP （100 μM）不能减弱CsA （100 μM）对bac诱导的MTP降低、细胞色素c水平和caspase-3活性升高的影响（p < 0.05）。CsA和CIP对caspase-3诱导的高通透性无效。结论CsA通过保护MTP减轻高通透性，从而阻止线粒体介导的凋亡信号传导。CsA的保护作用不依赖于钙调磷酸酶的抑制。
Background Mitochondria mediated apoptotic signaling contributes to microvascular hyperpermeability. We hypothesized that cyclosporine A (CsA), that protects mitochondrial transition pores would attenuate hyperpermeability independent of its calcineurin inhibitory property. Methods Hyperpermeability was induced in microvascular endothelial cell monolayers using pro-apoptotic BAK or active caspase-3 following CsA or a specific calcineurin inhibitor, calcineurin auto-inhibitory peptide (CIP) treatment. Permeability was measured based on FITC-albumin flux across the monolayers. Mitochondrial transmembrane potential (MTP) was determined using JC-1. Mitochondrial release of cytochrome c was measured using ELISA and caspase-3 activity fluorometrically. Results CsA (10 nM) but not CIP (100 μM) attenuated BAK-induced hyperpermeability (p < 0.05) CsA but not CIP attenuated BAK-induced decrease in MTP, increase in cytochrome c levels and caspase-3 activity (p < 0.05). CsA and CIP were ineffective against caspase-3-induced hyperpermeability. Conclusions CsA attenuated hyperpermeability by protecting MTP thus preventing mitochondria-mediated apoptotic signaling. CsA’s protective effect is independent of calcineurin inhibition.