tPA regulates pulmonary vascular activity through NMDA receptors.
tPA regulates pulmonary vascular activity through NMDA receptors.
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tPA 通过 NMDA 受体调节肺血管活性。
DOI：
10.1152/ajplung.00429.2010
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发表时间：
2011
期刊：
影响因子：
--
通讯作者：
Higazi,AbdAl-Roof
中科院分区：
文献类型：
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作者：
Nassar,Taher;Bdeir,Khalil;Yarovoi,Serge;Fanne,RamiAbu;Murciano,Juan-Carlos;Idell,Steven;Allen,TimothyCraig;Cines,DouglasB;Higazi,AbdAl-Roof
组织型纤溶酶原激活剂（tPA）是一种有效的纤溶酶，用于治疗急性冠状动脉阻塞。然而，tPA 在治疗由血栓性血管闭塞引起的其他疾病（例如肺栓塞）方面的效用有限。我们发现 tPA 对肺动脉环的收缩力产生剂量依赖性影响，这可能会影响其作为溶栓剂的有效性。在低浓度 (1 nM) 下，tPA 会刺激去氧肾上腺素的肺血管收缩，而在较高浓度 (20 nM) 下，tPA 会通过其“对接位点”与肺动脉表达的 N-甲基d-天冬氨酸受体 1 (NMDA-R1) 之间的相互作用抑制肺动脉收缩性并促进肺血管通透性。一种源自纤溶酶原激活剂抑制剂 1 型的六肽，可阻断 tPA 的对接位点，但不阻断其催化活性，抑制其与 NMDA-R1 的相互作用，消除对肺动脉收缩力的抑制，减弱血管通透性，并促进小鼠肺栓塞模型中的纤维蛋白溶解。使用缺乏对接位点但保留催化活性的 tPA 变体也得到了类似的结果。这些数据表明，减弱 tPA 的有害纤溶外效应并改善其在肺栓塞治疗中的益处：风险状况是可行的。
Tissue-type plasminogen activator (tPA) is a potent fibrinolytic enzyme used to treat acute coronary artery obstruction. However, tPA has shown limited utility in other disorders caused by thrombotic vascular occlusion, such as pulmonary embolism. We found that tPA caused dose-dependent effects on the contractility of pulmonary arterial rings that may affect its effectiveness as a thrombolytic agent. At low concentrations (1 nM), tPA stimulated pulmonary vascular contraction in response to phenylephrine, whereas at higher concentrations (20 nM) tPA inhibited pulmonary arterial contractility and promoted pulmonary vascular permeability through an interaction between its “docking site” andN-methyld-aspartate receptor type 1 (NMDA-R1) expressed by pulmonary arteries. A hexapeptide derived from plasminogen activator inhibitor type 1 that blocked the docking site of tPA, but not its catalytic activity, inhibited its interaction with NMDA-R1, abolished inhibition of pulmonary artery contractility, attenuated vascular permeability, and facilitated fibrinolysis in a murine model of pulmonary embolism. Similar outcomes were seen using a tPA variant that lacks the docking site but retains catalytic activity. These data suggest that it is feasible to attenuate the deleterious extrafibrinolytic effects of tPA and improve its benefit:risk profile in the management of pulmonary embolism.