MODULATION OF PROTEIN-C INHIBITOR ACTIVITY

Protein C inhibitor (PCI), antithrombin, and heparin cofactor II are m embers of the serine proteinase inhibitor (serpin) superfamily that in hibit proteinases at rates which increase in the presence of the glyco saminoglycan heparin. These studies were undertaken to understand how PCI activity is modulated by various substances that are found in or i nteract with the vascular endothelium/basement membrane. The effects o f antithrombin-heparin, thrombomodulin, vitronectin and leukocyte elas tase on PCI-thrombin and PCI-activated protein C (APC) interactions we re investigated. Antithrombin, which does not inhibit APC but which do es bind to heparin/heparan sulphate with higher affinity than PCI, cau sed only a small decrease in the inhibition rate of PCI-APC in the pre sence of unfractionated heparin. Thrombomodulin, a chondroitin sulphat e-containing proteoglycan, accelerated PCI inhibition of thrombin and APC. PCI-thrombin in the presence or absence of heparin bound plastic adsorbed vitronectin, but neither PCI alone nor PCI-APC bound. Vitrone ctin also decreased the inhibition rate of PCI-thrombin and PCI-APC in the presence of low concentrations of heparin. Leukocyte elastase pro teolytically inactivated PCI in a reaction that was accelerated by hep arin. Overall, these results indicate that PCI activity is modulated b y these endothelial cell/basement membrane-based substances in similar ways as other heparin-binding serpins, especially antithrombin.