Hepatocyte growth factor activator (HGFA): its regulation by protein C inhibitor

Protein C inhibitor (PCI; SERPINA5) is a plasma serine protease inhibitor, and a potent inhibitor of activated protein C (APC), which plays a critical role in the anticoagulant protein C pathway. Recently, PCI was also found to form a complex with the serine protease hepatocyte growth factor activator (HGFA), inhibiting the HGFA-catalyzed activation of the single-chain hepatocyte growth factor precursor. In vivo studies using human PCI-transgenic (hPCI-Tg) mice, which mimic PCI expression in humans, showed that the regeneration rate of the liver after partial hepatectomy was significantly impaired as compared with wild-type mice. The decreased liver regeneration in hPCI-Tg mice was restored by pretreatment with antibody against human PCI. Furthermore, APC protected hepatic nonparenchymal cells from thrombin-induced inflammation in vitro, suggesting that plasma PCI may inhibit the cytoprotective action of APC on hepatic cells in hPCI-Tg mice. It was shown that the levels of HGFA-PCI are increased in plasma of patients who have been subjected to hepatectomy, as compared with complex levels in the plasma of normal individuals. Thus, PCI may play a role as a potent inhibitor of HGFA and APC in plasma and/or at the sites of tissue injury in the regulation of tissue regeneration.