Department of Molecular Medicine (IMM-315), The Scripps Research Institute, La Jolla, California, USA.
Curr Opin Hematol. 2019 Sep;26(5):320-330. doi: 10.1097/MOH.0000000000000528.
Activated protein C (APC) is a homeostatic coagulation protease with anticoagulant and cytoprotective activities. Focusing on APC's effects in the brain, this review discusses three different scenarios that illustrate how APC functions are intimately affecting the physiology and pathophysiology of the brain.
Cytoprotective APC therapy holds promise for the treatment of ischemic stroke, and a recently completed trial suggested that cytoprotective-selective 3K3A-APC reduced bleeding in ischemic stroke patients. In contrast, APC's anticoagulant activity contributes to brain bleeding as shown by the disproportional upregulation of APC generation in cerebral cavernous malformations lesions in mice. However, too little APC generation also contributes to maladies of the brain, such as in case of cerebral malaria where the binding of infected erythrocytes to the endothelial protein C receptor (EPCR) may interfere with the EPCR-dependent functions of the protein C pathway. Furthermore, discoveries of new activities of APC such as the inhibition of the NLRP3-mediated inflammasome and of new applications of APC therapy such as in Alzheimer's disease and graft-versus-host disease continue to advance our knowledge of this important proteolytic regulatory system.
APC's many activities or lack thereof are intimately involved in multiple neuropathologies, providing abundant opportunities for translational research.
激活蛋白 C（APC）是一种具有抗凝和细胞保护作用的内源性凝血蛋白酶。本文聚焦于 APC 在大脑中的作用，讨论了三种不同的情况，说明了 APC 功能如何密切影响大脑的生理学和病理生理学。
细胞保护作用的 APC 治疗为缺血性脑卒中的治疗带来了希望，最近完成的一项试验表明，细胞保护作用选择性 3K3A-APC 可减少缺血性脑卒中患者的出血。相反，APC 的抗凝活性导致脑出血，如在小鼠脑海绵状血管畸形病变中 APC 生成的不成比例上调所示。然而，APC 生成太少也会导致大脑疾病，例如脑疟疾，其中感染的红细胞与内皮蛋白 C 受体（EPCR）的结合可能会干扰蛋白 C 途径的 EPCR 依赖性功能。此外，APC 的新活性的发现，如抑制 NLRP3 介导体炎性小体，以及 APC 治疗的新应用，如在阿尔茨海默病和移植物抗宿主病中的应用，不断推进我们对这一重要蛋白水解调节系统的认识。
APC 的多种活性或缺乏与多种神经病理学密切相关，为转化研究提供了丰富的机会。
