Modulation of protein C inhibitor activity.
Protein C inhibitor (PCI), antithrombin, and heparin cofactor II are members of the serine proteinase inhibitor (serpin) superfamily that inhibit proteinases at rates which increase in the presence of the glycosaminoglycan heparin. These studies were undertaken to understand how PCI activity is modulated by various substances that are found in or interact with the vascular endothelium/basement membrane. The effects of antithrombin-heparin, thrombomodulin, vitronectin and leukocyte elastase on PCI-thrombin and PCI-activated protein C (APC) interactions were investigated. Antithrombin, which does not inhibit APC but which does bind to heparin/heparan sulphate with higher affinity than PCI, caused only a small decrease in the inhibition rate of PCI-APC in the presence of unfractionated heparin. Thrombomodulin, a chondroitin sulphate-containing proteoglycan, accelerated PCI inhibition of thrombin and APC. PCI-thrombin in the presence or absence of heparin bound plastic absorbed vitronectin, but neither PCI alone nor PCI-APC bound. Vitronectin also decreased the inhibition rate of PCI-thrombin and PCI-APC in the presence of low concentrations of heparin. Leukocyte elastase proteolytically inactivated PCI in a reaction that was accelerated by heparin. Overall, these results indicate that PCI activity is modulated by these endothelial cell/basement membrane-based substances in similar ways as other heparin-binding serpins, especially antithrombin.
Neese
L L
LL
Department of Pathology, University of North Carolina at Chapel Hill, School of Medicine 27599.
Pratt
C W
CW
Church
F C
FC
D000818:Animals; D000991:Antithrombins / Q000378:metabolism / Q000494:pharmacology; D006023:Glycoproteins / Q000378:metabolism / Q000494:pharmacology; D006493:Heparin / Q000378:metabolism / Q000494:pharmacology; D015844:Heparin Cofactor II / Q000494:pharmacology; D006497:Heparan Sulfate / Q000378:metabolism; D006801:Humans; D019272:Leukocyte Elastase; D010196:Pancreatic Elastase / Q000378:metabolism / Q000494:pharmacology; D011486:Protein C / Q000037:antagonists & inhibitors*; D018046:Protein C Inhibitor / Q000378:metabolism / Q000494:pharmacology*; D011817:Rabbits; D013917:Thrombin / Q000378:metabolism / Q000494:pharmacology; D018180:Thrombomodulin / Q000378:metabolism; D019096:Vitronectin
D000991:Antithrombins; D006023:Glycoproteins; D006493:Heparin; D015844:Heparin Cofactor II; D006497:Heparan Sulfate; D019272:Leukocyte Elastase; D010196:Pancreatic Elastase; D011486:Protein C; D018046:Protein C Inhibitor; D013917:Thrombin; D018180:Thrombomodulin; D019096:Vitronectin