Characterization of a novel human protein C inhibitor (PCI) gene transgenic mouse useful for studying the role of PCI in physiological and pathological conditions

• Published in: Journal of thrombosis and haemostasis Vol. 2; no. 6; pp. 949 - 961
• Main Authors: Hayashi, T., Nishioka, J., Kamada, H., Asanuma, K., Kondo, H., Gabazza, E. C., Ido, M., Suzuki, K.
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Science Inc 01.06.2004
• Subjects: activated protein C; Animals; Blood Coagulation; Gene Expression Regulation; Humans; Inflammation; Lipopolysaccharides - pharmacology; Mice; Mice, Transgenic; Models, Animal; Protein C - antagonists & inhibitors; Protein C - pharmacology; protein C inhibitor; Protein C Inhibitor - genetics; Protein C Inhibitor - physiology; Tissue Distribution; tissue expression; transgenic mice
• ISSN: 1538-7933; 1538-7836; 1538-7836
• DOI: 10.1111/j.1538-7836.2004.00733.x

In humans, protein C inhibitor (PCI) is expressed in various tissues and present in many body fluids including plasma and seminal fluid. In rodents, PCI is expressed in reproductive organs only and is absent in plasma. In this study, we characterized the tissue expression and physiological role of PCI in novel human PCI gene transgenic (TG) mice. Northern blot and immunohistochemical analyses demonstrated that human PCI is expressed in liver hepatocytes, renal epithelial cells as well as heart, brain and reproductive organs of the TG mice. This PCI tissue distribution is similar to that found in humans. PCI in plasma of TG mice showed the same immunological and functional properties as human plasma PCI. Next, we evaluated the effect of PCI on coagulation, inflammation and tissue damage in lipopolysaccharide‐treated TG mice. The results suggested that PCI efficiently inhibits not only the anticoagulant and anti‐inflammatory activities of exogenously injected human activated protein C (APC) but also that of endogenously produced APC in mice with endotoxemia. These findings suggest that PCI exerts a procoagulant and proinflammatory effect by inhibiting APC. We believe our results also show how useful these TG mice may be for assessing the therapeutic effect of human APC in vivo and for evaluating the role of PCI in human physiological and pathological conditions.