Rijken D C, de Munk G A, Jie A F
TNO Institute of Ageing and Vascular Research (IVVO-TNO), Gaubius Laboratory, Leiden, The Netherlands.
Thromb Haemost. 1993 Nov 15;70(5):867-72.
In order to define the possible effects of heparin on the fibrinolytic system under physiological conditions, we studied the interactions of this drug with plasminogen and its activators at various ionic strengths. As reported in recent literature, heparin stimulated the activation of Lys-plasminogen by high molecular weight (HMW) and low molecular weight (LMW) two-chain urokinase-type plasminogen activator (u-PA) and two-chain tissue-type plasminogen activator (t-PA) 10- to 17-fold. Our results showed, however, that this stimulation only occurred at low ionic strength and was negligible at a physiological salt concentration. Direct binding studies were performed using heparin-agarose column chromatography. The interaction between heparin and Lys-plasminogen appeared to be salt sensitive, which explains at least in part why heparin did not stimulate plasminogen activation at 0.15 M NaCl. The binding of u-PA and t-PA to heparin-agarose was less salt sensitive. Results were consistent with heparin binding sites on both LMW u-PA and the amino-terminal part of HMW u-PA. Single-chain t-PA bound more avidly than two-chain t-PA. The interactions between heparin and plasminogen activators can occur under physiological conditions and may modulate the fibrinolytic system.
为了确定肝素在生理条件下对纤溶系统的可能影响，我们研究了该药物在不同离子强度下与纤溶酶原及其激活剂的相互作用。正如最近文献所报道的，肝素可使高分子量（HMW）和低分子量（LMW）双链尿激酶型纤溶酶原激活剂（u-PA）以及双链组织型纤溶酶原激活剂（t-PA）对赖氨酸纤溶酶原的激活作用增强10至17倍。然而，我们的结果表明，这种刺激仅在低离子强度下发生，而在生理盐浓度下可忽略不计。使用肝素-琼脂糖柱色谱进行直接结合研究。肝素与赖氨酸纤溶酶原之间的相互作用似乎对盐敏感，这至少部分解释了为什么肝素在0.15M NaCl时不会刺激纤溶酶原激活。u-PA和t-PA与肝素-琼脂糖的结合对盐不太敏感。结果与LMW u-PA和HMW u-PA氨基末端部分上的肝素结合位点一致。单链t-PA比双链t-PA结合更紧密。肝素与纤溶酶原激活剂之间的相互作用可在生理条件下发生，并可能调节纤溶系统。
