2016 Scientific Sessions Sol Sherry Distinguished Lecturer in Thrombosis: Thrombotic Stroke: Neuroprotective Therapy by Recombinant-Activated Protein C.
2016 Scientific Sessions Sol Sherry Distinguished Lecturer in Thrombosis: Thrombotic Stroke: Neuroprotective Therapy by Recombinant-Activated Protein C.
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DOI：
10.1161/atvbaha.116.308038
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发表时间：
2016-11
期刊：
影响因子：
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通讯作者：
Zlokovic BV
中科院分区：
文献类型：
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作者：
Griffin JH;Mosnier LO;Fernández JA;Zlokovic BV
活化蛋白C（APC）来源于血浆蛋白酶酶原蛋白C，具有抗血栓形成和抗炎作用。在临床前损伤模型中，重组APC为多种损伤提供神经保护，包括缺血性卒中。APC通过启动需要多种受体的细胞信号传导直接作用于脑内皮细胞和神经元。两种或多种主要的APC受体介导APC的神经保护细胞信号传导。当与内皮细胞蛋白C受体结合时，APC可以切割蛋白酶激活受体1，从而产生偏向的细胞保护信号，减少缺血诱导的损伤。在小鼠缺血性卒中研究中，药理学APC可预防组织纤溶酶原激活剂（tPA）诱导的出血。值得注意的是，APC的信号传导促进神经发生。APC的信号选择性重组变体“3 K3 A-APC”被工程化以缺乏APC的大部分抗凝活性，但保留APC的细胞信号传导作用。重组3 K3 A-APC正在进行NIH资助的缺血性卒中临床试验。
Activated protein C (APC), derived from the plasma protease zymogen, protein C, is antithrombotic and anti-inflammatory. In preclinical injury models, recombinant APC provides neuroprotection for multiple injuries, including ischemic stroke. APC acts directly on brain endothelial cells and neurons by initiating cell signaling that requires multiple receptors. Two or more major APC receptors mediate APC’s neuroprotective cell signaling. When bound to endothelial cell protein C receptor, APC can cleave protease activated receptor 1 causing biased cytoprotective signaling that reduces ischemia-induced injury. Pharmacologic APC alleviates bleeding induced by tissue plasminogen activator (tPA) in murine ischemic stroke studies. Remarkably, APC’s signaling promotes neurogenesis. The signaling-selective recombinant variant of APC, “3K3A-APC”, was engineered to lack most of APC’s anticoagulant activity but retain APC’s cell signaling actions. Recombinant 3K3A-APC is in ongoing NIH-funded clinical trials for ischemic stroke.