Inactivation of factor VIIa by antithrombin in vitro, ex vivo and in vivo: role of tissue factor and endothelial cell protein C receptor.
Inactivation of factor VIIa by antithrombin in vitro, ex vivo and in vivo: role of tissue factor and endothelial cell protein C receptor.
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DOI：
10.1371/journal.pone.0103505
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发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
Rao LV
中科院分区：
文献类型：
--
作者：
Vatsyayan R;Kothari H;Mackman N;Pendurthi UR;Rao LV
最近的研究表明，抗凝血酶（AT）可以作为一个重要的生理调节FVIIa。然而，体外研究表明，AT只有在与组织因子（TF）结合时才能有效抑制FVIIa。已知循环血液最多只含有微量的TF。FVIIa也结合内皮细胞蛋白C受体（EPCR），但EPCR对AT灭活FVIIa的作用尚不清楚。本研究旨在研究TF和EPCR在AT体内灭活FVIIa中的作用。通过尾静脉向低人TF小鼠（低TF，小鼠TF水平的约1%表达）和高人TF小鼠（HTF，小鼠TF水平的约100%）注射人rFVIIa（120 µg kg−1体重）。在rFVIIa给药后的不同时间间隔，采集血液以测量血浆中的FVIIa-AT复合物和rFVIIa抗原水平。尽管小鼠中TF表达存在较大差异，但与低TF小鼠相比，HTF小鼠仅产生多40-50%的FVIIa-AT复合物。通过LPS注射增加HTF小鼠体内TF的浓度使FVIIa-AT复合物的水平增加约25%。野生型、EPCR缺陷和EPCR过表达小鼠之间的FVIIa-AT水平无显著差异。体外和离体形成的FVIIa-AT复合物的水平远低于体内发现的水平。总之，我们的研究结果表明，在正常血管损伤期间短暂暴露的循环血液或血管外TF中可能存在的TF的痕迹有助于循环中AT对FVIIa的灭活。然而，TF在FVIIa的AT失活中的作用似乎是次要的，并且血浆中、血细胞或血管内皮上存在的其它因子可能在该过程中起主要作用。
Recent studies have suggested that antithrombin (AT) could act as a significant physiologic regulator of FVIIa. However, in vitro studies showed that AT could inhibit FVIIa effectively only when it was bound to tissue factor (TF). Circulating blood is known to contain only traces of TF, at best. FVIIa also binds endothelial cell protein C receptor (EPCR), but the role of EPCR on FVIIa inactivation by AT is unknown. The present study was designed to investigate the role of TF and EPCR in inactivation of FVIIa by AT in vivo. Low human TF mice (low TF, ∼1% expression of the mouse TF level) and high human TF mice (HTF, ∼100% of the mouse TF level) were injected with human rFVIIa (120 µg kg−1 body weight) via the tail vein. At varying time intervals following rFVIIa administration, blood was collected to measure FVIIa-AT complex and rFVIIa antigen levels in the plasma. Despite the large difference in TF expression in the mice, HTF mice generated only 40–50% more of FVIIa-AT complex as compared to low TF mice. Increasing the concentration of TF in vivo in HTF mice by LPS injection increased the levels of FVIIa-AT complexes by about 25%. No significant differences were found in FVIIa-AT levels among wild-type, EPCR-deficient, and EPCR-overexpressing mice. The levels of FVIIa-AT complex formed in vitro and ex vivo were much lower than that was found in vivo. In summary, our results suggest that traces of TF that may be present in circulating blood or extravascular TF that is transiently exposed during normal vessel damage contributes to inactivation of FVIIa by AT in circulation. However, TF’s role in AT inactivation of FVIIa appears to be minor and other factor(s) present in plasma, on blood cells or vascular endothelium may play a predominant role in this process.
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影响因子：
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作者：
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通讯作者：
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