Plasminogen activator inhibitor-1 is a major determinant of arterial thrombolysis resistance
Plasminogen activator inhibitor-1 is a major determinant of arterial thrombolysis resistance
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DOI：
10.1161/01.cir.99.23.3050
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发表时间：
1999-06-15
期刊：
影响因子：
37.8
通讯作者：
Fay, WP
中科院分区：
文献类型：
--
作者：
Zhu, YH;Carmeliet, P;Fay, WP
富血小板血栓对组织型纤溶酶原激活物（tPA）的溶解具有抵抗性，纤溶酶原激活物抑制剂-1（派-1）是tPA的快速抑制剂，可能是动脉血栓溶解抵抗的原因之一。然而，关于派-1对动物动脉血栓溶解的影响的数据很少。我们使用了a。小鼠颈动脉损伤模型以检验PAI-1抑制由药理学浓度的tPA介导的血栓溶解的假设，方法和结果：用氯化铁在野生型小鼠（派-1 +/+; n=11）和PAI-1缺陷型小鼠（PAI-1-/-; n=11）中诱导富含血小板的血栓。派-1 +/+和派-1 -/-小鼠之间的基线颈动脉血流量和平均闭塞时间没有差异。通过输注肝素（200 U/kg推注，70 U.kg（-1）.h（-1）滴注）、人纤溶酶原（50 mg/kg）和tPA（20（n=10）或100（n=12，）μ g.kg（-1）.min（-1））诱导凝块溶解。平均血浆tPA抗原为2.7 μ g/mL（tPA输注，20 μ g.kg（-1）.min（-1））和5.5 μ g/mL（tPA输注，100 μ g.kg（-1）.min（-1）），派-1 +/+小鼠和派-1 -/-小鼠之间无显著差异。tPA 20 μ g.kg（-1）.min（-1）后，5只PAI-1 +/+小鼠中有1只发生再灌注，而5只派-1 -/-小鼠中有5只发生再灌注（P=0.0006）。接受tPA 100 μg.kgmin的所有小鼠均发生再灌注，但PAI-1 -/-小鼠的再灌注时间（17.8+/-2.6分钟，n=6）明显短于派-1 +/+小鼠（35.7+/-5.1分钟，n =6; P=0.01）。组织学分析证实颈动脉血栓富含血小板，派-1均匀分布于派-1 +/+小鼠的整个血栓中。派-1 +/+血小板的裂解物抑制人tPA，而PAI-1-/-血小板裂解物doesn 't.Conclusions-PAI-1是一个主要的决定因素，富含血小板的动脉血栓溶解的药理浓度的tPA的阻力。抑制或抵抗派-1的策略可增强血栓溶解。
Background-Platelet-rich thrombi are resistant to lysis by tissue plasminogen activator (tPA), Plasminogen activator inhibitor-1 (PAI-1), a rapid inhibitor of tPA, may contribute to arterial thrombolysis resistance. However, few data are available regarding the effect of PAI-1 on arterial thrombolysis in animals. We used a. murine carotid injury model to test the hypothesis that PAI-I inhibits thrombolysis mediated by pharmacological concentrations of tPA.,Methods and Results-Platelet-rich thrombi were induced in wild-type mice (PAI-1 +/+; n=11) and PAI-l-deficient mice (PAI-I -/-; n=11) with ferric chloride. Baseline carotid blood flows and mean occlusion times did not differ between PAI-1 +/+ and PAI-1 -/- mice. Clot lysis was induced by infusion of heparin (200 U/kg bolus, 70 U.kg(-1).h(-1) drip), human plasminogen (50 mg/kg) and tPA at 20 (n=10) or 100 (n=12,) mu g.kg(-1).min(-1). Mean plasma tPA antigens were 2.7 mu g/mL (tPA infusion, 20 mu g.kg(-1).min(-1)) and 5.5 mu g/mL (tPA infusion, 100 mu g.kg(-1).min(-1)), with no significant differences between PAI-1 +/+ mice and PAI-1 -/- mice, Reperfusion after tPA 20 mu g.kg(-1).min(-1) occurred in 1 of 5 PAI-1 +/+ mice versus 5 of 5 PAI-1 -/- mice (P=0.0006). Reperfusion occurred in all mice that received tPA 100 mu g.kg(-1).min(-1), but reperfusion times were significantly shorter in PAI-1 -/- mice (17.8+/-2.6 minutes, n=6) than in PAI-1 +/+ mice (35.7+/-5.1 minute, n=6; P=0.01), Histological analyses confirmed that carotid thrombi were platelet rich and that PAI-1 was distributed uniformly throughout thrombi from PAI-1 +/+ mice. Lysates of PAI-1 +/+ platelets inhibited human tPA, whereas PAI-I -/- platelet lysates did not.Conclusions-PAI-1 is a major determinant of the resistance of platelet-rich arterial thrombi to lysis by pharmacological concentrations of tPA. Strategies to inhibit or resist PAI-1 may enhance thrombolysis.