INSERM U919 'serine proteases and pathophysiology of the neurovascular unit', UMR CNRS 6232 Cinaps, GIP Cyceron, University of Caen, 14032 Caen, France.
J Cell Sci. 2011 Jun 15;124(Pt 12):2070-6. doi: 10.1242/jcs.084392. Epub 2011 May 24.
Owing to its ability to generate the clot-dissolving protease plasmin, tissue plasminogen activator (tPA) is the only approved drug for the acute treatment of ischemic stroke. However, tPA also promotes hemorrhagic transformation and excitotoxic events. High mobility group box-1 protein (HMGB-1) is a non-histone transcription factor and a pro-inflammatory cytokine, which has also been shown to bind to both tPA and plasminogen. We thus investigated the cellular and molecular effects through which HMGB-1 could influence the vascular and parenchymal effects of tPA during ischemia. We demonstrate that HMGB-1 not only increases clot lysis by tPA, but also reduces the passage of vascular tPA across the blood-brain barrier, as well as tPA-driven leakage of the blood-brain barrier. In addition, HMGB-1 prevents the pro-neurotoxic effect of tPA, by blocking its interaction with N-methyl-D-aspartate (NMDA) receptors and the attendant potentiation of NMDA-induced neuronal Ca²⁺ influx. In conclusion, we show in vitro that HMGB-1 can promote the beneficial effects of tPA while counteracting its deleterious properties. We suggest that derivatives of HMGB-1, devoid of pro-inflammatory properties, could be used as adjunctive therapies to improve the overall benefit of tPA-mediated thrombolysis following stroke.
由于能够生成溶解血栓的蛋白酶纤溶酶原激活物（tPA），组织型纤溶酶原激活物（tPA）是唯一批准用于急性缺血性脑卒中治疗的药物。然而，tPA 也会促进出血性转化和兴奋性毒性事件。高迁移率族蛋白 B1（HMGB-1）是一种非组蛋白转录因子和促炎细胞因子，也已被证明与 tPA 和纤溶酶原结合。因此，我们研究了 HMGB-1 通过何种细胞和分子机制影响 tPA 在缺血期间的血管和实质作用。我们证明 HMGB-1 不仅可以增加 tPA 的血栓溶解作用，还可以减少血管型 tPA 通过血脑屏障的通透性，以及 tPA 驱动的血脑屏障渗漏。此外，HMGB-1 通过阻止 tPA 与 N-甲基-D-天冬氨酸（NMDA）受体相互作用，并减轻 NMDA 诱导的神经元 Ca²⁺内流，从而防止 tPA 的神经毒性作用。总之，我们在体外证明 HMGB-1 可以促进 tPA 的有益作用，同时抵消其有害作用。我们认为，HMGB-1 的衍生物，无促炎特性，可以用作辅助治疗，以提高中风后 tPA 介导的溶栓的整体益处。
