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3-O sulfation of heparin leads to hepatotropism and longer circulatory half-life.
Thrombosis Research ( IF 3.7 ) Pub Date : 2018-05-25 , DOI: 10.1016/j.thromres.2018.05.018
Colton M Miller 1 , Yongmei Xu 2 , Katrina M Kudrna 1 , Blake E Hass 1 , Brianna M Kellar 1 , Andrew W Egger 1 , Jian Liu 2 , Edward N Harris 1
Affiliation  

INTRODUCTION Heparins are common blood anticoagulants that are critical for many surgical and biomedical procedures used in modern medicine. In contrast to natural heparin derived from porcine gut mucosa, synthetic heparins are homogenous by mass, polymer length, and chemistry. MATERIALS & METHODS Stable cell lines expressing the human and mouse Stabilin receptors were used to evaluate endocytosis of natural and synthetic heparin. We chemoenzymatically produced synthetic heparin consisting of 12 sugars (dodecamers) containing 14 sulfate groups resulting in a non-3-O sulfated structure (n12mer). Half of the n12mer was modified with a 3-O sulfate on a single GlcNS sugar producing the 3-O sulfated heparin (12mer). Wildtype (WT), Stabilin-1 knock-out (KO), and Stabilin-2 KO C57BL/6 mice were developed and used for metabolic studies and provided as a source for primary liver sinusoidal endothelial cells. RESULTS & CONCLUSIONS Human and mouse Stabilin-2 receptors had very similar endocytosis rates of both the 12mer and n12mer, suggesting that they are functionally similar in primary cells. Subcutaneous injections of the n12mer and 12mer revealed that the 12mer had a much longer half-life in circulation and a higher accumulation in liver. The n12mer never accumulated in circulation and was readily excreted by the kidneys before liver accumulation could occur. Liver sinusoidal endothelial cells from the Stabilin-2 KO mice had lower uptake rates for both dodecamers, whereas, the Stabilin-1 KO mice had lower endocytosis rates for the 12mer than the n12mer. 3-O sulfation of heparin is correlated to both a longer circulatory half-life and hepatotropism which is largely performed by the Stabilin receptors.

中文翻译:

肝素的3-O硫酸盐化可导致肝硬化和更长的循环半衰期。

简介肝素是常见的血液抗凝剂,对于现代医学中使用的许多外科手术和生物医学手术来说至关重要。与衍生自猪肠粘膜的天然肝素相反,合成肝素在质量,聚合物长度和化学性质上均一。材料与方法表达人和小鼠稳定蛋白受体的稳定细胞系用于评估天然和合成肝素的内吞作用。我们用化学酶法生产的合成肝素由12个糖(十二聚体)组成,含有14个硫酸根基团,形成非3-O硫酸盐结构(n12mer)。将n12mer的一半在单个GlcNS糖上用3-O硫酸盐修饰,生成3-O硫酸化肝素(12mer)。野生型(WT),Stabilin-1基因敲除(KO),开发了Stabilin-2 KO C57BL / 6小鼠和Stabilin-2 KO C57BL / 6小鼠,并将其用作原发性肝窦内皮细胞的来源。结果与结论人和小鼠Stabilin-2受体的12mer和n12mer内吞率非常相似,表明它们在原代细胞中的功能相似。皮下注射n12mer和12mer揭示了12mer具有更长的循环半衰期和更高的肝脏蓄积性。n12mer从未在循环中积聚,在肝脏积聚之前很容易被肾脏排泄。Stabilin-2 KO小鼠的肝窦窦内皮细胞对两种十二聚体的摄取率均较低,而Stabilin-1 KO小鼠的12mer内吞率低于n12mer。
更新日期:2019-11-01
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