Activated protein C utilizes the angiopoietin/Tie2 axis to promote endothelial barrier function
Activated protein C utilizes the angiopoietin/Tie2 axis to promote endothelial barrier function
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DOI：
10.1096/fj.09-134445
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发表时间：
2010-03-01
期刊：
影响因子：
4.8
通讯作者：
Jackson, Christopher J.
中科院分区：
文献类型：
--
作者：
Minhas, Nikita;Xue, Meilang;Jackson, Christopher J.
活化蛋白C（APC）是一种抗凝剂，被批准用于治疗严重脓毒症，可以防止细胞凋亡，炎症和血管渗漏。本研究的目的是探讨APC是否通过血管生成素（Ang）/Tie 2轴保护内皮屏障功能。APC以剂量（0.01-10 μ g/ml）和时间（0.5- 24 h）依赖的方式显著上调人脐静脉内皮细胞（HUVECs）Tie 2和Ang 1基因和蛋白的表达。有趣的是，它显著抑制Ang 2，IC 50接近0.1 μ g/ml。在APC存在下，使用Evans蓝染料转移测量的HUVEC渗透性显著降低，并且与对照相比，紧密连接相关蛋白紧密连接蛋白（ZO）-1上调并定位于细胞周围的外周。与未受刺激的细胞相比，平滑肌细胞向APC刺激的HUVECs的迁移升高。与同种型（IgG）或乱序siRNA对照相比，阻断抗体和小干扰（si）RNA处理表明APC需要3种受体，即内皮蛋白C受体、蛋白酶激活受体1和Tie 2来执行所有这些屏障稳定功能。总之，这项研究表明APC对Ang/Tie 2轴具有新的作用，这增强了内皮屏障功能，并可能有助于其在败血症和其他与血管渗漏相关的疾病中的治疗效果。Minhas，N.，薛，M.，Fukudome，K.，杰克逊角J.活化蛋白C利用血管生成素/Tie 2轴促进内皮屏障功能。FASEB J.24，873-881（2010）。www.fasebj.org
Activated protein C (APC) is an anticoagulant, approved as a treatment for severe sepsis, that can prevent apoptosis, inflammation, and vascular leakage. The aim of this study was to investigate whether APC protects endothelial barrier function through the angiopoietin (Ang)/Tie2 axis. APC significantly up-regulated gene and protein expression of Tie2 and Ang1 in a dose (0.01-10 mu g/ml)- and time (0.5-24h)-dependent manner in human umbilical vein endothelial cells (HUVECs). Interestingly, it markedly inhibited Ang2 with an IC50 of similar to 0.1 mu g/ml. HUVEC permeability, measured using Evans blue dye transfer, was significantly reduced in the presence of APC, and, in concordance, the tight junction associated protein zona occludens (ZO)-1 was up-regulated and localized peripherally around cells, compared with controls. Smooth muscle cell migration toward APC-stimulated HUVECs was elevated compared with un-stimulated cells. Blocking antibodies and small interfering (si) RNA treatment, compared with isotype (IgG) or scrambled siRNA controls, showed that APC requires 3 receptors, the endothelial protein C receptor, protease-activated receptor 1, and Tie2 to perform all these barrier stabilization functions. In summary, this study demonstrates that APC has novel effects on the Ang/Tie2 axis, which enhance endothelial barrier function and are likely to contribute to its therapeutic effect in sepsis and other diseases associated with vascular leakage.-Minhas, N., Xue, M., Fukudome, K., Jackson, C. J. Activated protein C utilizes the angiopoietin/Tie2 axis to promote endothelial barrier function. FASEB J. 24, 873-881 (2010). www.fasebj.org