Griffin John H, Zlokovic Berislav V, Mosnier Laurent O
Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, CA; Division of Hematology-Oncology, Department of Medicine, University of California, San Diego, San Diego, CA; and.
Zilkha Neurogenetic Institute, Keck School of Medicine, University of Southern California, Los Angeles, CA.
Blood. 2015 May 7;125(19):2898-907. doi: 10.1182/blood-2015-02-355974. Epub 2015 Mar 30.
The homeostatic blood protease, activated protein C (APC), can function as (1) an antithrombotic on the basis of inactivation of clotting factors Va and VIIIa; (2) a cytoprotective on the basis of endothelial barrier stabilization and anti-inflammatory and antiapoptotic actions; and (3) a regenerative on the basis of stimulation of neurogenesis, angiogenesis, and wound healing. Pharmacologic therapies using recombinant human and murine APCs indicate that APC provides effective acute or chronic therapies for a strikingly diverse range of preclinical injury models. APC reduces the damage caused by the following: ischemia/reperfusion in brain, heart, and kidney; pulmonary, kidney, and gastrointestinal inflammation; sepsis; Ebola virus; diabetes; and total lethal body radiation. For these beneficial effects, APC alters cell signaling networks and gene expression profiles by activating protease-activated receptors 1 and 3. APC's activation of these G protein-coupled receptors differs completely from thrombin's activation mechanism due to biased signaling via either G proteins or β-arrestin-2. To reduce APC-associated bleeding risk, APC variants were engineered to lack >90% anticoagulant activity but retain normal cell signaling. Such a neuroprotective variant, 3K3A-APC (Lys191-193Ala), has advanced to clinical trials for ischemic stroke. A rich data set of preclinical knowledge provides a solid foundation for potential translation of APC variants to future novel therapies.
内稳态血液蛋白酶——活化蛋白C（APC），可发挥以下作用：（1）基于对凝血因子Va和VIIIa的失活作用，作为一种抗血栓形成物质；（2）基于内皮屏障稳定以及抗炎和抗凋亡作用，作为一种细胞保护物质；（3）基于对神经发生、血管生成和伤口愈合的刺激作用，作为一种再生物质。使用重组人源和鼠源APC的药物治疗表明，APC为一系列截然不同的临床前损伤模型提供了有效的急性或慢性治疗方法。APC可减轻以下因素所致的损伤：脑、心脏和肾脏的缺血/再灌注；肺部、肾脏和胃肠道炎症；脓毒症；埃博拉病毒；糖尿病；以及全身致死性辐射。由于APC通过激活蛋白酶激活受体1和3来改变细胞信号网络和基因表达谱，从而产生这些有益作用。APC对这些G蛋白偶联受体的激活机制与凝血酶完全不同，这是因为其通过G蛋白或β-抑制蛋白2产生偏向性信号传导。为降低与APC相关的出血风险，对APC变体进行了改造，使其抗凝活性降低>90%，但保留正常的细胞信号传导功能。这样一种具有神经保护作用的变体，即3K3A-APC（赖氨酸191-193突变为丙氨酸），已进入缺血性中风的临床试验阶段。丰富的临床前知识数据集为将APC变体转化为未来新型疗法奠定了坚实基础。
