Modulation of blood coagulation and fibrinolysis by polyamines in the presence of glycosaminoglycans
Modulation of blood coagulation and fibrinolysis by polyamines in the presence of glycosaminoglycans
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DOI：
10.1016/j.biocel.2005.04.014
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发表时间：
2005-09-01
影响因子：
4
通讯作者：
Igarashi, K
中科院分区：
文献类型：
--
作者：
Homma, R;Mase, A;Igarashi, K
研究了在糖胺聚糖 (GAG) 存在下多胺对血液凝固和纤维蛋白溶解的影响，因为已知肝素 (HP) 会与多胺（尤其是精胺）相互作用。精胺能逆转HP引起的家兔血浆凝固时间的延长。然后使用合成底物测试了抗凝血酶 III (AT) 存在下各种 GAG 对凝血酶活性的影响。 GAG对凝血酶活性的抑制顺序为HP>硫酸乙酰肝素(HS)>硫酸皮肤素(DS)>>与透明质酸(HA)一致的硫酸软骨素(CS)。当这些GAG完全磺化时，HS、DS、CS和HA的抑制活性变得更强，但HP则没有。 GAG 对凝血酶活性的影响可以被多胺（尤其是精胺）逆转。精胺逆转HP抑制的EC50值为30-50μM，精胺对抗肝素的K-d值为41.1μM。表面等离子共振(SPR)分析表明，精胺通过与HP结合减弱了AT和HP之间的相互作用。然后检查 HP 对纤维蛋白溶解的影响。当使用谷氨酸纤溶酶原和组织型纤溶酶原激活剂（tPA）作为酶源时，HP强烈增强纤溶酶活性，而精胺则逆转了这种作用。 SPR分析表明，tPA活性位点的结构可能是通过tPA、HP和精胺形成三元复合物而改变的。结果表明，在HP存在下，精胺增强了血液凝固，削弱了纤维蛋白溶解。 (C) 2005 Elsevier Ltd. 保留所有权利。
The effects of polyamines on blood coagulation and fibrinolysis in the presence of glycosaminoglycans (GAGs) were examined because it is known that heparin (HP) interacts with polyamines, especially with spermine. Spermine was able to reverse the prolongation of coagulation time of rabbit plasma caused by HP. The effects of various GAGs on thrombin activity in the presence of anti-thrombin III (AT) were then tested using a synthetic substrate. Inhibition of thrombin activity by GAGs was in the order HP>heparan sulfate (HS)>dermatan sulfate (DS)>>chondroitin sulfate (CS)congruent to hyaluronan (HA). When these GAGs were fully sulfonated, the inhibitory activity of HS, DS, CS and HA, but not HP, became stronger. The effects of GAGs on thrombin activity were reversed by polyamines, in particular spermine. The EC50 value of spermine for reversal of HP inhibition was 30-50 mu M, and the K-d value of spermine for heparin was 41.1 mu M. Analysis by surface plasmon resonance (SPR) indicated that the interaction between AT and HP was weakened by spermine through its binding to HP. The effect of HP on fibrinolysis was then examined. When Glu-plasminogen and tissue-type plasminogen activator (tPA) were used as enzyme source, HP strongly enhanced the plasmin activity and spermine reversed this effect. Analysis by SPR suggests that the structure of the active site of tPA may be changed through the ternary complex formation of tPA, HP and spermine. The results indicate that blood coagulation was enhanced and fibrinolysis was weakened by spermine in the presence of HP. (C) 2005 Elsevier Ltd. All rights reserved.