Analysis of Protein C Inhibitor/ SERPINA5

Protein C inhibitoru (PCI), serin proteaz ailesinden (SERPINA5) α1 proteaz inhibitior prototipinde bir plazma glikoproteinidir. Ilk olarak insan plazmasinda aktive protein C inhibitoru olarak daha sonra ise koagulasyon ve fibrinolizisin inhibitoru olarak tanimlanmistir. PCI, idrardan sekrete olur ve urokinaz tipi plazminojen aktivatoru (uPA) ile kompleks olusturur.  Bu nedenle plazminojen aktivator inhibitoru 3 (PAI-3) olarak da bilinir. PCI’nin tromboz ve fibrinoliziste, fertilizasyonun duzenlenmesinde, doku rejenerasyonunda, vaskuler permeabilitede, tumor gelisimi, invazyon, metastaz ve anjiyogenezin duzenlenmesinde rol oynadigi bilinmektedir Bu derlemede; PCI'in islevleri hakkinda bilgi vermek ve ileride yapilacak calismalar icin rehberlik saglamak amaclanmistir.


Introduction
Protein C inhibitor (PCI) is a plasma glycoprotein in the alpha 1 protease inhibitor prototype from the serine protease family (SERPINA5). It was first described by Marlar and Griffin as an inhibitor of human blood plasma-activated protein C (APC) and later as an inhibitor of coagulation and fibrinolysis.
PCI is secretory from the urine ( 250ng/ml) and complexes with the urokinase-type plasminogen activator (uPA). This is also known as plasminogen activator inhibitor 3 (PAI-3). PCI has heparin binding properties and therefore other protease inhibitors are in the class of heparin-binding serpins such as antithrombin (ATIII) and heparin cofactor II (HCII). Heparin is a negatively charged glycosaminoglycan, secreted by mast cells and a small amount of basophils. Heparin has the task of removing thrombin and complexing with antithrombin III; afterwards at the coagulation cascade of FXa, FXa, FXa and FXA and is in contact with the basic residues of PCI. Heparin does not stimulate PCI inhibition of plasma kallikrein, PSA and HGFA . [1][2][3]Active Protein C (APC) inhibition can be achieved with 5-10 u / ml heparin. PCI is a good inhibitor of thrombin besides being an APC inhibitor in the hemostatic system; Procoagulant with APC inhibition and anticoagulant with thrombin inhibition. PCI inhibits its target proteases by forming SDS stable 1:1 complexes.

Functions of Protein C Inhibitor
In humans, PCI concentration is in plasma at approximately 4 μg/mL concentration and is thought to originate from the liver. Human PCI is expressed in many organs and tissues, and the protein is present in most body fluids and secretions. PCI expression has been shown in the liver, in the kidney, in the skin , in the heart and in the male and female reproductive tracts [4] Studies of mice known to be extrinsic to the reproductive organs of the PCI in rodents have revealed PCI expression patterns during mouse development. According to this, it was determined that PCI expression was common in the brain ventricles, in the heart, in the urogenital system, in the skeletal muscles and cartilaginous. [5][6][7][8] The appearance of PCI expression in lung development suggests that PCI may play a role in lung morphogenesis and angiogenesis. The demonstration that PCI plays a role in tissue growth and regeneration by acting as an inhibitor on the activator of the hepatocyte growth factor demonstrates the importance of PCI in cellular processes such as growth signaling.

Protein C Inhibitor at Thrombosis and Hemostasis
Protein C is converted to active protein C (APC) by the binding of thrombin to vascular endothelium. An active protein C resistance (APCR) occurs in the presence of point mutation in the factor V gene. The mutation result is the abnormal Factor V, the factor V Leiden (3). Active protein C resistance is the most common hereditary coagulation defect associated with venous thrombosis. This molecular defect is found in 20-40% of patients with deep vein thrombosis . [9] Patients with deep vein thrombosis and pulmonary embolism were found to have α-1 antitrypsin with APC and PCI complex, indicating that the regulation of the protein C system under pathological conditions is by PCI.
PCI; In the inhibition of coagulation enzymes, the anticoagulant acts as an inhibitor of APC-Protein C, which is activated by thrombin-thrombomodulin, and in the antifibrinolytic role in the inhibition of urokinase . [10] Furthermore, a significant increase in plasma concentrations of active SERPINA5 has been described in people with myocardial infarction and is seen as a risk marker for acute coronary events. SERPINA5 is defined in complex with proteases, in patients with active coagulation, and in patients receiving thrombolytic therapy, demonstrating that SERPINA5 reacts in vivo with the proteases of the hemostatic system. However, it is questioned how much it contributes to the regulation of hemostasis . [11]

Protein C Inhibitor in Pulmonary Arterial Hypertension
Pulmonary arterial hypertension (PAH), which causes recurrent pulmonary embolisms and heart failure, is a rare disease with a frequency of one millionth. .Pulmonary arterial hypertension (PAH) is group 1 pulmonary hypertension (PH), which has nothing to do with pulmonary embolism or chronic thromboembolic pulmonary disease.
Whereas chronic thromboembolic pulmonary disease may result in precapillary PH, which is group 4 PH and also called chronic thromboembolic pulmonary hypertension (CTEPH). Interestingly, PAH could be associated with in situ thrombosis in the distal pulmonary arteries . [12]. The excess coagulation defect caused by protein C deficiency is a rare cause of pulmonary embolism. Nishii et al. In a study conducted with PCI transgenic mice, it has been shown that PCI reduces the effect of pulmonary hypertension through thrombin inhibition . [13]

PCI in Tissue Repair and Regeneration
PCI is making tissue repair and regeneration by regulating the hepatocyte growth factor activator. Hepatocyte growth factor (HGF) plays a critical role in tissue regeneration proliferation, providing stimulation of endothelial and epithelial motility of various cell types. HGF is synthesized in hepatocytes and is in the form of proHGF inactive form. Thrombin is responsible for the activation of proHGFA to HGFA. PCI inhibits HGFA by forming an enzyme-inhibitor complex. The role of PCI in tissue regeneration, repair and wound healing through the inhibition of HGF activity suggests that it may be a potential target for lung regeneration therapy . [14][15][16]  In vivo SERPINA5 could bind to glycosaminoglycans on cell surfaces as well as to phospholipids exposed on atherosclerotic plaques on apoptotic and/or activated cells [23], and on microparticles.

Cancer & PCI
It is known that PCI (Serpin A5) plays a protective role against tumor development, tumor invasion and tumor metastasis.
The various single nucleotide changes (SNPs) identified in the SERPINA5 gene have been found to be associated with the risk of papillary and follicular thyroid cancer. Expression of SERPINA5 appears to be more benign in uterine cancer, while SERPINA5 is suppressed in more aggressive tumors.
Several ex vivo and preclinical studies have been performed to analyze the role of SERPINA5 in tumor cell proliferation, migration, metastasis formation, and tumor angiogenesis, and SERPINA5 does not exhibit malignant behavior in these studies. However, the mechanism of these effects has not yet been met. It appears that not all activities are dependent on protease inhibition activity [24][25]

PCI as a Proteomic Target
When PCI is examined for protein technology; two types of proteomic analysis have been shown to be potential

Results
Though studies that initially identified the inhibitors of APC and fibrinolysis, and later studies have shown that Protein C inhibitor (PCI), which is known to play a role in many mechanisms ranging from fertilization to cancer, is not only effective in thrombosis and hemostasis, the underlying factors are not fully understood. This deficiency will be overcome with new research on PCI, which is known to have multifunctionality.