Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, CA 92037, USA.
J Thromb Haemost. 2013 Jun;11 Suppl 1(0 1):242-53. doi: 10.1111/jth.12247.
The protein C pathway provides multiple important functions to maintain a regulated balance between hemostasis and host defense systems in response to vascular and inflammatory injury. The anticoagulant protein C pathway is designed to regulate coagulation, maintain the fluidity of blood within the vasculature, and prevent thrombosis, whereas the cytoprotective protein C pathway prevents vascular damage and stress. The cytoprotective activities of activated protein C (APC) include anti-apoptotic activity, anti-inflammatory activity, beneficial alterations of gene expression profiles, and endothelial barrier stabilization. These cytoprotective activities of APC, which require the endothelial protein C receptor (EPCR) and protease-activated receptor-1 (PAR1), have been a major research focus. Recent insights, such as non-canonical activation of PAR1 at Arg46 by APC and biased PAR1 signaling, provided better understanding of the molecular mechanisms by which APC elicits cytoprotective signaling through cleavage of PAR1. The discovery and development of anticoagulant-selective and cytoprotective-selective APC mutants provided unique opportunities for preclinical research that has been and may continue to be translated to clinical research. New mechanisms for the regulation of EPCR functionality, such as modulation of EPCR-bound lipids that affect APC's cytoprotective activities, may provide new research directions to improve the efficacy of APC to convey its cytoprotective activities to cells. Moreover, emerging novel functions for EPCR expand the roles of EPCR beyond mediating protein C activation and APC-induced PAR1 cleavage. These discoveries increasingly develop our understanding of the protein C pathway, which will conceivably expand its physiological implications to many areas in the future.
蛋白 C 途径提供了多种重要功能，以维持血管和炎症损伤时止血和宿主防御系统之间的调节平衡。抗凝蛋白 C 途径旨在调节凝血、维持血管内血液的流动性并预防血栓形成，而细胞保护蛋白 C 途径则可防止血管损伤和应激。活化蛋白 C（APC）的细胞保护活性包括抗凋亡活性、抗炎活性、有益的基因表达谱改变和内皮屏障稳定。这些 APC 的细胞保护活性需要内皮蛋白 C 受体（EPCR）和蛋白酶激活受体-1（PAR1），一直是主要的研究重点。最近的研究进展，如 APC 对 PAR1 的 Arg46 的非经典激活和偏向性 PAR1 信号转导，为 APC 通过切割 PAR1 引发细胞保护信号的分子机制提供了更好的理解。抗凝选择性和细胞保护选择性 APC 突变体的发现和开发为临床前研究提供了独特的机会，这些研究可能会继续转化为临床研究。EPCR 功能调节的新机制，如调节影响 APC 细胞保护活性的 EPCR 结合脂质，可能为提高 APC 将其细胞保护活性传递给细胞的功效提供新的研究方向。此外，EPCR 的新兴新功能将 EPCR 的作用扩展到了介导蛋白 C 激活和 APC 诱导的 PAR1 切割之外。这些发现越来越深入地了解了蛋白 C 途径，这在未来可能会扩展其生理意义到许多领域。
