Cheng Tong, Liu Dong, Griffin John H, Fernández José A, Castellino Francis, Rosen Elliot D, Fukudome Kenji, Zlokovic Berislav V
Frank P. Smith Neurosurgical Research Laboratory, Department of Neurosurgery and Center for Aging and Developmental Biology, Division of Neurovascular Biology, University of Rochester Medical Center, Rochester, New York, USA.
Nat Med. 2003 Mar;9(3):338-42. doi: 10.1038/nm826. Epub 2003 Feb 3.
Activated protein C (APC) is a systemic anti-coagulant and anti-inflammatory factor. It reduces organ damage in animal models of sepsis, ischemic injury and stroke and substantially reduces mortality in patients with severe sepsis. It was not known whether APC acts as a direct cell survival factor or whether its neuroprotective effect is secondary to its anti-coagulant and anti-inflammatory effects. We report that APC directly prevents apoptosis in hypoxic human brain endothelium through transcriptionally dependent inhibition of tumor suppressor protein p53, normalization of the pro-apoptotic Bax/Bcl-2 ratio and reduction of caspase-3 signaling. These mechanisms are distinct from those involving upregulation of the genes encoding the anti-apoptotic Bcl-2 homolog A1 and inhibitor of apoptosis protein-1 (IAP-1) by APC in umbilical vein endothelial cells. Cytoprotection of brain endothelium by APC in vitro required endothelial protein C receptor (EPCR) and protease-activated receptor-1 (PAR-1), as did its in vivo neuroprotective activity in a stroke model of mice with a severe deficiency of EPCR. This is consistent with work showing the direct effects of APC on cultured cells via EPCR and PAR-1 (ref. 9). Moreover, the in vivo neuroprotective effects of low-dose mouse APC seemed to be independent of its anti-coagulant activity. Thus, APC protects the brain from ischemic injury by acting directly on brain cells.
活化蛋白C（APC）是一种全身性抗凝和抗炎因子。它可减轻脓毒症、缺血性损伤和中风动物模型中的器官损伤，并显著降低严重脓毒症患者的死亡率。此前尚不清楚APC是作为直接的细胞存活因子发挥作用，还是其神经保护作用继发于其抗凝和抗炎作用。我们报告称，APC通过转录依赖性抑制肿瘤抑制蛋白p53、使促凋亡的Bax/Bcl-2比值正常化以及减少半胱天冬酶-3信号传导，直接预防缺氧人脑内皮细胞的凋亡。这些机制不同于APC在脐静脉内皮细胞中上调编码抗凋亡Bcl-2同源物A1和凋亡抑制蛋白-1（IAP-1）的基因所涉及的机制。APC在体外对脑内皮细胞的细胞保护作用需要内皮蛋白C受体（EPCR）和蛋白酶激活受体-1（PAR-1），其在EPCR严重缺乏的小鼠中风模型中的体内神经保护活性也是如此。这与表明APC通过EPCR和PAR-1对培养细胞具有直接作用的研究结果一致（参考文献9）。此外，低剂量小鼠APC的体内神经保护作用似乎与其抗凝活性无关。因此，APC通过直接作用于脑细胞来保护大脑免受缺血性损伤。
