COMPLEMENTARY MODES OF ACTION OF TISSUE-TYPE PLASMINOGEN-ACTIVATOR AND PRO-UROKINASE BY WHICH THEIR SYNERGISTIC EFFECT ON CLOT LYSIS MAY BE EXPLAINED
COMPLEMENTARY MODES OF ACTION OF TISSUE-TYPE PLASMINOGEN-ACTIVATOR AND PRO-UROKINASE BY WHICH THEIR SYNERGISTIC EFFECT ON CLOT LYSIS MAY BE EXPLAINED
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DOI：
10.1172/jci113394
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发表时间：
1988-03-01
影响因子：
15.9
通讯作者：
GUREWICH, V
中科院分区：
文献类型：
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作者：
PANNELL, R;BLACK, J;GUREWICH, V
研究了组织型纤溶酶原激活剂(t-PA)和/或尿激活酶原(Pro-UK)对血浆中悬浮的标准125I-纤维蛋白凝块的溶解作用。剂量被控制在非特异性影响的浓度以下，即观察到纤维蛋白原溶解和主要的纤溶酶原消耗。少量的t-PA通过减弱前UK的滞后期特征而增强了Pro-UK对血栓的溶解，并导致更早地过渡到溶解的快速阶段。当血栓用UK或少量纤溶酶(<；1%血栓溶解)预处理时，也能获得类似的促进尿激酶原的纤溶作用。纤溶酶的促进作用被随后用羧肽酶B处理的凝块所抵消，这表明纤溶酶的作用与纤维蛋白上的羧基末端赖氨酸残基的暴露有关。这些赖氨酸末端不存在于未降解的纤维蛋白中，是纤溶酶原与纤维蛋白高亲和力结合所必需的。相反，t-PA对凝块的溶解不受纤溶酶预处理的影响，也几乎不受纤维蛋白底物的羧基肽酶B处理的影响。因此，与纤维蛋白赖氨酸末端结合的纤溶酶原，尽管被发现对尿蛋白原是必需的，但似乎并不是t-PA的底物。纤维蛋白结合的纤溶酶原的选择性激活归因于结合引起的谷氨酸纤溶酶原构象的变化。目前的发现表明，当纤溶酶原与末端赖氨酸结合而不是与内部赖氨酸结合时，这种构象变化就会发生。纤溶酶原结合到纤维蛋白上的后一个部位，被t-PA激活，因此参与了三元复合体。这启动了未降解的凝块的溶解，并暴露了PRO-UK所需的纤溶酶原结合部位。通过纤维蛋白结合的纤溶酶原的互补激活，t-PA和Pro-UK可以诱导有效和协同的纤溶作用，而单独使用时效率相对较低。
Tissue plasminogen activator (t-PA) and/or pro-urokinase (pro-UK) induced lysis of standard 125I-fibrin clots suspended in plasma was studied. Doses were kept below the concentration at which a nonspecific effect was seen, i.e., where fibrinogenolysis and major plasminogen consumption were observed. Small amounts of t-PA potentiated clot lysis by pro-UK by attenuating the lag phase characteristic of pro-UK, and causing a much earlier transition to the rapid phase of lysis. Similar promotion of the fibrinolytic effect of pro-UK was obtained when clots were pretreated with UK or with a little plasmin (< 1% clot lysis). Promotion by plasmin was nullified by a subsequent treatment of the clot with carboxypeptidase B, indicating that the plasmin effect was related to the exposure of carboxy terminal lysine residues on fibrin. These lysine termini, absent in undegraded fibrin, are known to be essential for the high affinity binding of plasminogen to fibrin. In contrast, clot lysis by t-PA was unaffected by plasmin pretreatment and little affected by carboxypeptidase B treatment of the fibrin substrate. Therefore, plasminogen bound to lysine termini on fibrin, although found to be essential for pro-UK, did not appear to serve as a substrate for t-PA. Selective activation of fibrin bound plasminogen has been attributed to the conformational change in Glu-plasminogen that occurs as a result of binding. The present findings suggest that this conformational change occurs when plasminogen is bound to a terminal lysine but not to an internal lysine. Plasminogen bound to the latter site on fibrin was activated by t-PA and therefore is involved in the ternary complex. This initiates lysis of the undegraded clot and exposes the plasminogen binding sites required by pro-UK. By their complementary activation of fibrin bound plasminogen, t-PA followed by pro-UK induces efficient and synergistic fibrinolysis, whereas each is relatively inefficient when used alone.