Characterization of transgenic mice that secrete functional human protein C inhibitor into the circulation

Protein C inhibitor (PCI) is a heparin binding serine protease inhibitor in plasma, which exerts procoagulant activity by inhibiting thrombomodulin-bo und thrombin or activated protein C (APC). Since the role of PCI in vivo is largely unknown we generated genetically modified mice with expression of human PCI mRNA in hepatocytes only. Three transgenic lines have been charac terized. Transgenic mice did not show gross developmental abnormalities. Tw o lines showed a pericentral and one line showed a periportal expression pa ttern of human PCI mRNA in the liver. Genetically modified mice secreted a functional transgenic protein into the circulation (3-5 mu g/ml plasma in h eterozygous mice and 10 mu g/ml in homozygous mice), which inhibited human APC activity in the presence of heparin. interestingly, transgenic mice in which human PCI was expressed periportally in the liver had the highest spe cific activity. Endogenous mouse PCI mRNA could only be detected in the mal e and female reproductive system, but not in the liver, indicating that end ogenous PCI levels in the circulation are low or even absent in mice. These results demonstrate that the human PCI transgenic mice are a suitable mode l for studying the in vivo role of PCI in blood coagulation.