Low-Molecular Weight Heparin Increases Circulating sFlt-1 Levels and Enhances Urinary Elimination
Low-Molecular Weight Heparin Increases Circulating sFlt-1 Levels and Enhances Urinary Elimination
复制标题
DOI：
10.1371/journal.pone.0085258
复制
发表时间：
2014-01-21
期刊：
影响因子：
3.7
通讯作者：
Brinkkoetter, Paul T.
中科院分区：
文献类型：
--
作者：
Hagmann, Henning;Bossung, Verena;Brinkkoetter, Paul T.
基本原理：先兆子痫是一种毁灭性的医学妊娠并发症，导致孕产妇和胎儿的发病率和死亡率。虽然先兆子痫的病因尚不清楚，但人类和动物研究表明，可溶性fms样酪氨酸激酶-1（sFlt-1）（VEGF受体1的一种选择性剪接变体）的循环水平过高，导致先兆子痫的体征和症状。由于sFlt-1与肝素和硫酸乙酰肝素蛋白聚糖结合，我们推测妊娠期常用的抗凝肝素可能会干扰sFlt-1在体内的水平、分布和消除。目的：我们系统地测定了先兆子痫妇女在给予低分子量肝素前后血清和尿液中血管生成因子的水平，并进一步表征了低分子量肝素与血管生成因子的相互作用，方法和结果：血清和尿液样品用于测量肝素施用之前和之后的sFlt-1水平。孕妇肝素给药后血清sFlt-1水平升高25%。循环sFlt-1增加的幅度与初始sFlt-1血清水平相关。肝素给药后尿sFlt-1水平也升高，消除水平取决于肾小球滤过屏障的基本完整性。采用阳离子交换色谱的生化结合研究表明，肝素结合的sFlt-1具有降低的亲和力，带负电荷的表面相比，sFlt-1单独。结论：低分子量肝素管理增加循环sFlt 1水平和增强肾脏消除。我们提供的证据表明，这两种影响可能是由于肝素结合sFlt 1和掩蔽sFlt 1蛋白的正电荷。
Rationale: Preeclampsia is a devastating medical complication of pregnancy which leads to maternal and fetal morbidity and mortality. While the etiology of preeclampsia is unclear, human and animal studies suggest that excessive circulating levels of soluble fms-like tyrosine-kinase-1 (sFlt-1), an alternatively spliced variant of VEGF-receptor1, contribute to the signs and symptoms of preeclampsia. Since sFlt-1 binds to heparin and heparan sulfate proteoglycans, we hypothesized that the anticoagulant heparin, which is often used in pregnancy, may interfere with the levels, distribution and elimination of sFlt-1 in vivo.Objective: We systematically determined serum and urine levels of angiogenic factors in preeclamptic women before and after administration of low molecular weight heparin and further characterized the interaction with heparin in biochemical studies.Methods and Results: Serum and urine samples were used to measure sFlt-1 levels before and after heparin administration. Serum levels of sFlt-1 increased by 25% after heparin administration in pregnant women. The magnitude of the increase in circulating sFlt-1 correlated with initial sFlt-1 serum levels. Urinary sFlt-1 levels were also elevated following heparin administration and levels of elimination were dependent on the underlying integrity of the glomerular filtration barrier. Biochemical binding studies employing cation exchange chromatography revealed that heparin bound sFlt-1 had decreased affinity to negatively charged surfaces when compared to sFlt-1 alone.Conclusion: Low molecular weight heparin administration increased circulating sFlt1 levels and enhanced renal elimination. We provide evidence that both effects may be due to heparin binding to sFlt1 and masking the positive charges on sFlt1 protein.