Griffin John H, Mosnier Laurent O, Fernández José A, Zlokovic Berislav V
From the Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, CA (J.H.G., L.O.M., J.A.F.); Division of Hematology/Oncology, Department of Medicine, University of California, San Diego (J.H.G.); and Department of Physiology and Biophysics, Zilkha Neurogenetic Institute, Keck School of Medicine, University of Southern California, Los Angeles (B.V.Z.).
Arterioscler Thromb Vasc Biol. 2016 Nov;36(11):2143-2151. doi: 10.1161/ATVBAHA.116.308038. Epub 2016 Oct 6.
APC (activated protein C), derived from the plasma protease zymogen, 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. Pharmacological APC alleviates bleeding induced by tissue-type plasminogen activator 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 the APC's anticoagulant activity but retain APC's cell signaling actions. Recombinant 3K3A-APC is in ongoing National Institutes of Health (NIH)-funded clinical trials for ischemic stroke.
活化蛋白C（APC）源自血浆蛋白酶原，具有抗血栓形成和抗炎作用。在临床前损伤模型中，重组APC可为多种损伤提供神经保护，包括缺血性中风。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。两种或更多种主要的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可切割蛋白酶激活受体1，引发偏向性的细胞保护信号传导，从而减少缺血性损伤。在小鼠缺血性中风研究中，药理学上的APC可减轻组织型纤溶酶原激活剂引起的出血。值得注意的是，APC的信号传导可促进神经发生。APC的信号传导选择性重组变体3K3A-APC经过改造，使其大部分抗凝活性缺失，但保留了APC的细胞信号传导作用。重组3K3A-APC正在美国国立卫生研究院（NIH）资助的缺血性中风临床试验中。
