The multi‐functional serpin, protein C inhibitor: beyond thrombosis and hemostasis

Abstract

Summary. Protein C inhibitor (PCI) is a member of the serine protease inhibitor (serpin) family. PCI was initially found to be an inhibitor of activated protein C, and later shown to be a potent inhibitor of blood coagulation and fibrinolysis such as that mediated by urokinase type‐plasminogen activator. Therefore, the protein came to be known as plasminogen activator inhibitor‐3. It also inhibits proteases involved in fertilization. PCI is broadly conserved, and is found in human, rhesus monkey, cow, rabbit, rat, mouse and chicken. The human PCI gene is located on chromosome 14q32.1 in a cluster of genes encoding related serpins. Sp1‐ and AP2‐binding sites in the 5′‐flanking region act as promoter and enhancer, respectively, for its expression in the liver. PCI mRNA is expressed in many organs in primates, but only in the reproductive organs in rodents. Recent studies using transgenic mice expressing the human gene have suggested that PCI is also involved in regulation of lung remodeling, tissue regeneration, vascular permeability, proteolysis in the kidney and tumor cell invasion. A protease inhibitor‐independent activity of PCI, the prevention of anti‐angiogenesis and metastasis of tumor cells, has also been observed. Thus, PCI is a unique multi‐functional serpin playing diverse roles in the thrombosis and hemostasis in multiple organs and tissues of a variety of species.

N-glycans of Human Protein C Inhibitor: Tissue-Specific Expression and Function

“…The rate for PSA inhibition by PCI is thus very low compared to the inhibition of other seminal serine proteases, although a large proportion of PCI in seminal plasma forms a complex with PSA. Similar observations have been reported previously and are presumably due to the high concentration of PSA in semen [2], [5]. Moreover, N-glycans alone did not significantly contribute to the k 2 for PCI inhibition of PSA.…”

“…Protein C inhibitor (PCI) is a 57 kD glycoprotein that belongs to the serine protease inhibitor (Serpin) superfamily of proteins, and exists in many tissues and fluids in humans, including reproductive organs, semen, blood, urine, breast milk and skin [1], [2]. PCI found in blood originates from the liver and is capable of inhibiting several serine proteases involved in the regulation of coagulation and fibrinolysis, including activated protein C, thrombin, factor Xa, various kallikreins and plasminogen activators.…”

“…PCI found in blood originates from the liver and is capable of inhibiting several serine proteases involved in the regulation of coagulation and fibrinolysis, including activated protein C, thrombin, factor Xa, various kallikreins and plasminogen activators. Additionally, PCI has been found to have antimicrobial and antitumor properties and thus appears to be a medically interesting versatile protein [2].…”

The Extrinsic Coagulation Pathway: a Biomarker for Suicidal Behavior in Major Depressive Disorder

“…TFPI upregulation indicates inhibition of the TF-FVIIa complex and FXa, while PCI downregulation indicates disinhibition of FXa (Figs 3 and 5). APC upregulation is likely a result of the downregulation of PCI39. These findings may also explain conflicting previous studies regarding the expression of coagulative factors in depressed patients2526272829, as prior studies failed to selectively enroll or analytically distinguish depressed suicidal attempters and non-attempters.…”

“…APC, another inhibitor of coagulation that was significantly increased in MDD-SA relative to MDD-NA and HC subjects, cleaves and inhibits FVa38. PCI, another inhibitor of coagulation that was significantly decreased in MDD-SA relative to MDD-NA and HC subjects, inhibits FXa and is the primary inhibitor of APC in human plasma39. Finally, F1 + 2 – the byproduct of prothrombin’s conversion to thrombin that is considered to be a reliable marker of the circulating thrombin levels40 – was significantly upregulated in MDD-SA compared to MDD-NA subjects and downregulated in MDD-SA compared to HC.…”