Sulfation patterns in heparin and heparan sulfate: effects on the proliferation of bovine pulmonary artery smooth muscle cells
Sulfation patterns in heparin and heparan sulfate: effects on the proliferation of bovine pulmonary artery smooth muscle cells
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DOI：
10.1016/j.bbadis.2003.09.002
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发表时间：
2003-11-20
影响因子：
6.2
通讯作者：
Linhardt, RJ
中科院分区：
文献类型：
--
作者：
Garg, HG;Yu, LY;Linhardt, RJ
肝素（HP）对平滑肌细胞的抗增殖作用对于确定治疗肺动脉高压的新方法具有潜在的重要意义。市售的HP和硫酸肝素（HS）在结构上是异相聚合物。为了研究哪些磺酸基团是内源性抗增殖活性所必需的，我们制备了以下6个化学修饰的猪粘膜HP和HS，它们分为三组。一组是完全o -磺化- n -乙酰化，第二组是去n -磺化和再n -乙酰化，第三组是6- o -脱硫的HP和HS衍生物。测定了6种制剂对牛肺动脉平滑肌细胞的抗增殖作用。实验结果表明(a) HP和HS的过o -磺化增加了抗增殖活性，(b)用n -乙酰基取代己糖胺降低了HP和HS的抗增殖活性，(c) HP和HS的6- o -磺化降低了抗增殖能力。令人惊讶的是，在给定的硫酸化水平下存在的醛酸残留物的类型对抗增殖效力并不重要。综上所述，只有O-和n -磺基取代水平与HP和HS的抗增殖活性有良好的相关性。(C) 2003 Elsevier B.V.版权所有
Heparin's (HP's) antiproliferative effect on smooth muscle cells is potentially important in defining new approaches to treat pulmonary hypertension. The commercially available HP and heparan sulfate (HS) are structurally heterogenous polymers. In order to examine which sulfonate groups are required for endogenous antiproliferative activity, we prepared the following six chemically modified porcine mucosal HP and HS, which fell into three groups. One group consisted of fully O-sulfonated-N-acetylated, the second group consisted of de-N-sulfonated and re-N-acetylated, and the third group consisted of 6-O-desulfonated HP and HS derivatives. These six preparations were assayed for their antiproliferative potency on bovine pulmonary artery smooth muscle cells. The results of this assay show that (a) over-O-sulfonation of both HP and HS increases antiproliferative activity, (b) substitution of hexosamine with N-acetyl diminishes antiproliferative activity in both HP and HS, and (c) 6-O-desulfonation of HP and HS diminishes antiproliferative potency. Surprisingly, the type of uronic acid residue present at a given level of sulfation is unimportant for antiproliferative potency. In conclusion, only the level of O- and N-sulfo group substitution correlates well with HP and HS antiproliferative activity. (C) 2003 Elsevier B.V. All rights reserved.