Tissue plasminogen activator neurovascular toxicity is controlled by activated protein C
Tissue plasminogen activator neurovascular toxicity is controlled by activated protein C
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DOI：
10.1038/nm1122
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发表时间：
2004-12-01
期刊：
影响因子：
82.9
通讯作者：
Zlokovic, BV
中科院分区：
文献类型：
--
作者：
Liu, D;Cheng, T;Zlokovic, BV
虽然组织纤溶酶原激活剂（tPA）的血栓溶解作用是有益的，但其神经毒性（1-5）是有问题的。在此，我们报告了tPA通过将凋亡途径从半胱天冬酶-9转移至半胱天冬酶-8（其直接激活半胱天冬酶-3，而不通过BID介导的线粒体途径扩增），增强缺血性人脑内皮细胞和N-甲基-D-天冬氨酸（NMDA）处理的小鼠皮质神经元的凋亡（6）。在体内，tPA诱导的小鼠脑缺血性损伤减少了半胱天冬酶-8抑制剂的脑室内给药，但不是由半胱天冬酶-9抑制剂，在对照组中，半胱天冬酶-9抑制剂，但不是半胱天冬酶-8抑制剂，是保护性的。活化蛋白C（APC）是一种具有抗凝、抗炎和抗凋亡活性的丝氨酸蛋白酶（7），在短暂缺血期间具有神经保护作用（8，9），并通过直接作用于内皮（9-11）和神经元（12）促进脑细胞中抗凋亡机制的激活，在体外和体内阻断tPA血管和神经元毒性。APC抑制tPA诱导的caspase-8激活内皮细胞caspase-3和caspase-3依赖的NMDA处理的神经元凋亡诱导因子核转位，并减轻tPA介导的小鼠脑缺血损伤。数据表明，tPA转移的凋亡信号在应激脑细胞从内在的外源性途径，需要半胱天冬酶-8。APC阻断tPA的神经血管毒性，并可能大大增加tPA治疗中风的有效性。
Although thrombolytic effects of tissue plasminogen activator (tPA) are beneficial, its neurotoxicity(1-5) is problematic. Here, we report that tPA potentiates apoptosis in ischemic human brain endothelium and in mouse cortical neurons treated with N-methyl-D-aspartate (NMDA) by shifting the apoptotic pathways from caspase-9 to caspase-8, which directly activates caspase-3 without amplification through the Bid-mediated mitochondrial pathway(6). In vivo, tPA-induced cerebral ischemic injury in mice was reduced by intracerebroventricular administration of caspase-8 inhibitor, but not by caspase-9 inhibitor, in contrast to controls in which caspase-9 inhibitor, but not caspase-8 inhibitor, was protective. Activated protein C (APC), a serine protease with anticoagulant, anti-inflammatory and antiapoptotic activities(7), which is neuroprotective during transient ischemia(8,9) and promotes activation of antiapoptotic mechanisms in brain cells by acting directly on endothelium(9-11) and neurons(12), blocked tPA vascular and neuronal toxicities in vitro and in vivo. APC inhibited tPA-induced caspase-8 activation of caspase-3 in endothelium and caspase-3-dependent nuclear translocation of apoptosis-inducing factor in NMDA-treated neurons and reduced tPA-mediated cerebral ischemic injury in mice. Data suggest that tPA shifts the apoptotic signal in stressed brain cells from the intrinsic to the extrinsic pathway which requires caspase-8. APC blocks tPA's neurovascular toxicity and may add substantially to the effectiveness of tPA therapy for stroke.