Plasminogen Activator Inhibitor-1
Plasminogen activator inhibitor; PAI; PAI-1; PLANH1; Plasminogen activator inhibitor 1; Serine (or cysteine) proteinase inhibitor, clade E (nexin, plasminogen activator inhibitor type 1), member 1; Serpin E1; Serpin peptidase inhibitor, clade E (nexin, plasminogen activator inhibitor type 1), member 1; SERPINE1
BMAL-1 : ARNTL; Aryl Hydrocarbon Receptor Nuclear Translocator Like
tPA : tissue plasminogen acitvator, PLAT; Plasminogen Activator, Tissue Type
uPA : PLAU; Plasminogen Activator, urokinase-type plasminogen activator
The fibrinolysis complex includes a serine protease inhibitor (SERPIN), type-1 plasminogen activator inhibitor (PAI-1), and its target serine proteinases, the urokinase, and tissue-type plasminogen activators (uPA and tPA). As serine proteases, uPA and tPA coordinate various physiological functions, including digestion, blood coagulation, and extracellular matrix regulation (Hedstrom 2002).
Plasmin is the principle enzyme of fibrinolysis. PAI-1 controls the critical step in fibrinolysis as inhibiting the plasminogen activator and blocks the formation of plasmin from plasminogen. In addition to fibrinolysis and blood coagulation, PAI-1 as a serine protease has well-characterized roles in diverse cellular activities, including wound healing, organ fibrosis, aging, autophagy, digestion, immune responses, tumor invasion, and metastasis (Durand et al. 2004; Wang et al. 2014; Flevaris and Vaughan 2017; Kortlever et al. 2006; Balsara and Ploplis 2008). PAI-1 has also been utilized as a biomarker of cardiovascular health and endothelial function: as elevated levels of PAI-1 associate with insulin resistance, metabolic syndrome, and diabetes (Bulut et al. 2016; Kaji 2016; Sobel et al. 1998). Several studies have indicated that PAI-1 plays crucial roles in insulin actions on liver, muscle, and fat (Kaji 2016; Sobel et al. 1998).
The pathophysiology of complex diseases such as atherosclerosis and cancer involves inflammatory processes with interaction of several cytokines and chemokines. Several experimental and clinical observations indicate that PAI-1 plays a major role in the onset of vascular disease and cancer.
The large majority of clinical adverse events in atherosclerosis uniformly involve intra-arterial thrombus formation, arterial closure, and resultant tissue necrosis. The fibrinolytic system is crucial in atherosclerosis as most of the clinical end points result from intravascular thrombosis. Myocardial infarction and stroke remain to be the leading causes of mortality. The process of fibrinolysis starts with conversion of an inactive proenzyme, plasminogen, a 92 kD single chain glycoprotein consisting of 791 amino acids into the active enzyme, plasmin (Forsgren et al. 1987). As in plasminogen activating thrombolytic therapy, the goal is to degrade fibrin and dissolve blood clots in the circulation. PAI-1 is the important determinant of the success after thrombolytic therapy (Kurnik 1995).
Given the wide array of biological functions, the activity of serine proteases is meticulously regulated. In case of fibrinolysis, this is perfectly achieved by a molecular switch mechanism of initial protease activation, and the activation of its inhibitor, PAI-1. Thus, the main event in fibrinolysis is plasminogen activation, which is tightly regulated at numerous control points. The recent protein structure determinations of the components of the fibrinolytic system have provided novel insights into the molecular mechanisms of plasminogen activation.
Simultaneously, plasminogen activators (PA) and plasminogen activator inhibitors (PAI-1) exist in blood and regulate the conversion of plasminogen to plasmin in a delicate balance with each other. Plasminogen activator inhibitor-1 (PAI-1) is the primary inhibitor of PAs, which convert plasminogen into plasmin, a critical protease involved in fibrinolysis. PAI-1 induces fibrinogenesis by suppressing intravascular and tissue fibrinolysis. Tissue-type plasminogen activator (tPA) and urokinase-type plasminogen activator (uPA) are the two physiologic plasminogen activators identified in blood. Both molecules are used for thrombolysis in clinical practice. tPA-mediated plasminogen activation results in the dissolution of fibrin at the site of vascular injury, whereas uPA activates cell-bound plasminogen by binding to a specific cellular receptor (u-PAR). Several other plasminogen activator inhibitors (PAI) have been identified, including PAI-1, PAI-2, PAI-3, and protease-nexin (Kruithof 1988). The significance of other plasminogen activator inhibitors remains to be elucidated.
The PAI-1 molecule is the most extensively studied and understood plasminogen activator inhibitor. PAI-1 and PAI-2 regulate the fibrinolysis. PAI-1 inhibits both tPA and uPA, whereas PAI-2 inhibits only uPA. PAI-3, which is also known as protein C inhibitor (PCI), is involved in coagulation, fibrinolysis, cancer, wound healing, and fertility. The biological function of PCI is still on research due to broad enzyme specificity, its wide tissue distribution (Meijers and Herwald 2011). Protease nexin 1 is an efficient inhibitor of uPA, thrombin, and plasmin. In addition to removing fibrin from the circulation, the fibrinolytic system also plays a role in other biological processes including inflammation, tumorigenesis, tissue remodeling, angiogenesis, arteriosclerosis, ovulation, embryogenesis, and neointima proliferation (Davis 1997; Draxler and Medcalf 2015).
PAI-1 Structure, a Member of Serine Protease Inhibitor (SERPIN) Family
PAI-1 is a glycoprotein from the serine protease inhibitor (serpin) family and the main inhibitor of tPA and uPA. As discussed, the enzymes of the fibrinolytic system are serine proteases characterized by the presence of a serine residue in the catalytic domain. The structure of PAI-1 is important in interpreting its function. The active site of the serine protease is located in the COOH terminal, and the NH2 terminal is the functional domain enabling the molecule to perform its dynamic cellular effects. Several biological functions of the activity of serine proteases are meticulously regulated at tight control points. Serpins act as molecular switch mechanisms to turn the initial protease activation on and off. Given the importance of PAI-1 in hemostasis, its activity in circulation is controlled by the conformational change in its unique tertiary structure. The structure of PAI-1 includes a reactive central loop which forms complexes with plasminogen activators. In the active form, the reactive central loop that mimics the peptide of plasminogen activator is exposed to bind the target serine protease. Binding to vitronectin stabilizes PAI-1 and extends its activity. Whereas in the latent form the reactive center loop is hidden inside. Upon binding to the reactive center loop (RCL) of PAI-1, plasminogen activators cut the PAI-1 molecule at the P1-P1′. This dynamic conformational change displaces the RCL into the core of the protein. In the mature form, PAI-1 is a 379 amino acid protein with a molecular mass of 42.7 kD (Ginsburg et al. 1986; Declerck et al. 1988). Stabilization of PAI-1 by vitronectin has profound impact in understanding its role in complex diseases such as cancer. The stability of PAI-1 is as important as plasma levels given the structure and function relationship of the molecule.
PAI-1 is synthesized from the endothelial cells as an active molecule, but it then spontaneously converts to a latent form which can be partially reactivated in vitro (Hekman and Loskutoff 1985). Partially explaining the function, PAI-1 has three specific protein-binding domains. The important first domain is the reactive center loop (RCL). This loop determines the function by binding to the plasminogen activator (PA). The second one determines the stability by the vitronectin binding. The domain comprised of helix D (hD), helix E (hE), and helix F (hF). A third domain exists which is within the hD and hE. The third domain interestingly binds to the low-density lipoprotein receptor-related protein (LRP1) (Placencio and DeClerck 2015).
Source of Circulating PAI-1
The source of PAI-1 has been an active area of research in complex diseases such as atherosclerosis. PAI-1 has been shown to be actively synthesized by several tissues. PAI-1 was first isolated from endothelial cells (Loskutoff et al. 1983) and hepatoma cells (Coleman et al. 1982) in animal models. PAI-1 is present in plasma and platelets and also expressed by variety of tissues (Kruithof et al. 1984, 1986; Erickson et al. 1984). Platelets store large amounts of PAI-1 in the α-granules. PAI-1 is present in platelets and in plasma, and PAI-1 level in plasma is a biomarker of atherothrombosis. Inactive (latent) PAI-1 is stored in the platelets. Platelet activation also activates PAI-1 and PAI-1 is released in large amounts (Nordenhem and Wiman 1997). Endothelial cell is a major source of plasma PAI-1 explaining the role of PAI-1 as a biomarker of endothelial dysfunction (Schleef and Loskutoff 1988).
In the endemic obesity era, adipose tissue has endocrine function and serves as a source of adipokines. Considerable interest remains by the identification of PAI-1 messenger RNA (mRNA) in fat tissue. PAI-1 is identified in various tissues and interacts with various growth factors, cytokines, and hormones. Adipose tissue was first described as a potent source of PAI-1 by Loskutoff group (Sawdey and Loskutoff 1991). Adipocyte-derived PAI-1, predominantly expressed in visceral fat, is released into the circulation in parallel with increased fat mass, and it functions as a crucial adipokine that negatively affects physiological metabolism and vascular biology. Clinical and experimental studies provide a link between the increased body fat of obesity and elevated plasma PAI-1. Accumulated fat and enhanced adipose tissue-derived PAI-1 are harbingers of metabolic syndrome, type 2 diabetes mellitus endothelial dysfunction, and increased cardiometabolic risk (Agirbasli 2005). The association between inflammation and atherosclerosis is well known. Inflammatory cytokines induce PAI-1 expression. Cell culture studies in 3T3 cells show a correlation between TGFb-stimulated elevations in PAI-1 mRNA and release of PAI-1 protein into the conditioned medium (Lundgren et al. 1996).
In addition to fibrinolysis, PAI-1 regulates cell migration by competing for a specific integrin binding site for vitronectin (Stefansson and Lawrence 1996). Several different forms of PAI-1 have been identified. Active form is secreted by cells and forms a stoichiometric 1:1 complex with the plasminogen activators. The activity of PAI-1 is the crucial component of fibrinolytic system as the active conformation of the PAI-1 is the least stable. At room temperature, active form loses activity spontaneously with a functional half-life of 2 h at 37 °C (Hekman and Loskutoff 1985). The in vitro half-life (T1/2) of PAI-1 activity is reported to be between 1 and 2 h (Lawrence et al. 1994).
Active PAI-1 in plasma is very sensitive to oxidation and stabilized by noncovalent association with vitronectin (Lindahl et al. 1989; Yasar Yildiz et al. 2014). Transgenic animal model that expresses a highly stable form of PAI-1 displays spontaneous thrombosis (Eren et al. 2002). Half-lives of recombinant PAI-1 variants constructed with random mutagenesis may change according to the type of mutation, so does the functional stability (Berkenpas et al. 1995).
Both functional stability and plasma levels are important components of fibrinolysis. The normal plasma antigen and activity levels of PAI-1 are widely distributed in normal physiology. To understand its complexity, PAI-1 activity levels range from 0 to 50 U/ml with antigen levels from few to 100 ng/ml. The significance of such wide variation in normal physiology is still poorly understood. From a functional stand point, PAI-1 activity indicates the unit of PAI-1 that neutralizes tPA. In normal physiology, there is excess of PAI-1 in circulation to inhibit the plasminogen activation (Chandler. 1991). Thus, fibrinolysis is repressed and the most tPA in plasma is bound to PAI-1 in the inactive form. The fast and adaptive nature of fibrinolysis components enables the system to change dynamically in response to stimuli.
Platelets and endothelial cells might be the source of plasma PAI-1. Recent studies indicate that the cellular source of PAI-1 can be determined by its tissue-specific glycosylation pattern (Brogren et al. 2008). In this study, no glycans were detected on PAI-1 isolated from plasma or platelets from healthy lean individuals. Platelets might be the main source of PAI-1 in lean subjects; on the other hand, PAI-1 from obese subjects had a glycan composition similar to that of adipose tissue. Other tissues (i.e., fat) contribute to PAI-1 in plasma in obese subjects with elevated PAI-1 levels.
Genetics of PAI-1
SERPINE1 gene resides on Chromosome 7 (7q21.3-q22), is approximately 12.2 kb long, and contains nine exons (Klinger et al. 1987). Site-specific mutations or polymorphisms in the promoter region alter the responsiveness of the gene. There are inconsistent results in studies of sequence variations within the genes related to hemostatic imbalance and their impact on coronary artery disease in different populations (Taymaz et al. 2007). Among the studied single nucleotide polymorphisms (SNPs) in PAI-1 gene, the most prominent one is 1 bp guanine deletion/insertion 4G/5G polymorphism in 675 bp upside of transcription start side. It is defined as a risk factor for vascular dieseases, especially myocardial infarction or increases coronary artery disease susceptibility. The 4G allele is associated with higher plasma PAI-1 expression and activity (Eriksson et al. 1995). Conflicting results have been reported on the association of 4G allele with PAI-1 expression from different populations. These observations indicate that gene-gene and gene-environment interactions exist in the control of PAI-1 gene expression. In SNP studies, genetic interactions among high risk alleles associate with the severity of coronary artery disease (Agirbasli et al. 2006). Although PAI-1 is known to be highly heritable, the variations in PAI-1 and the associated genes only explain a limited portion of this heritability (White et al. 2015). Transcription of PAI-1 is regulated by renin angiotensin system, glucose, diurnal variation, hormones, and cytokines (Eren et al. 2003; Vaughan 2005).
Studies have shown PAI-1 mRNA in several tissues (Vaughan 1998). The major producers are hepatocytes, vascular endothelial and smooth muscle cells, adipocytes, and platelets (Erickson et al. 1985; Sawdey and Loskutoff 1991; Busso et al. 1994; Alessi et al. 1997). In addition, PAI-1 expression in humans is under circadian control, with peak expression in the morning (Maemura et al. 2000; Angleton et al. 1989; Kurnik 1995). Cardiovascular events such as myocardial infarction cumulate at the early morning hours as the peak levels of PAI-1 occur in early morning hours. The circadian expression of PAI-1 gene is thought to be regulated by the circadian clock proteins such as CLOCK, BMAL1/BMAL2, and PER (Maemura et al. 2000, 2007; Huang et al. 2012). Circadian clock is found to be associated with diabetes- and obesity-induced PAI-1 gene expression. CLOCK gene mutations affect PAI-1 levels and circadian clock proteins are important for hypofibrinolysis induced by metabolic disorders such as diabetes (Oishi 2009). New circadian clock genes variants (PER3) are found to be associated with PAI-1 expression in a population-specific manner (White et al. 2015; Ciarleglio et al. 2008).
Ongoing research about gene-gene interactions and differential impact of gene variants on PAI-1 expression may help us better understand the PAI-1 heritability. Future studies are needed to understand PAI-1 as a therapeutic target for the prevention or treatment of cardiovascular disease (Agirbasli. 2005).
Pro- and Antitumor Effects of PAI-1
PAI-1 and the fibrinolytic system have important functions within the vascular wall. PAI-1 also has a complex role in the development, spread, and prognosis of cancer. PAI-1 is elevated in various cancers, where it has been shown to effect metastasis and invasion to neighboring tissue and neovascularization. However, the exact nature of PAI-1 involvement in tumorigenesis and metastasis is far from being clear. Several paradoxical observations indicate a complex role of PAI-1 in tumor progression. It is intricate that PAI-1 is produced by both tumor and normal cells including endothelial or adipocytes in tumor microenvironment. PAI-1 expressed by cancer cells behaves differently than PAI-1 expressed on normal cells in terms of its effects on apoptosis (Lademann 2005; Balsara and Ploplis 2008).
PAI-1 is a negative regulator of cell growth, exerting its effect on the phosphatidylinositol 3-kinase/Akt pathway and allowing controlled cell proliferation. PAI-1 directly binds to caspases as a mechanism of PAI-1-mediated cellular apoptosis. PAI-1 inhibits activation of plasminogen by uPA or tPA, it is expected to inhibit tumor angiogenesis and growth. However, increased level of PAI-1 is an indicator of poor prognosis in cancer. It is stated that the absence of extracellular PAI-1 in tumor cells results in higher levels of activated caspase 9. Thus, the effects of PAI-1 on the cellular apoptosis are still a subject of debate. Furthermore, unlike circulating PAI-1, its intercellular levels are increased in cancer cells. The effects of intracellular PAI-1 in cancer formation and progression remain to be elucidated.
As a molecular switch mechanism, PAI-1 can regulate both cell death and survival. For instance, evidence suggests that PAI-1 alters key signaling pathways involved in maintaining endothelial cell integrity thereby regulating cell death (i.e., PI3-k/Akt and the Jak/STAT) (Balsara and Ploplis 2008). To further demonstrate its complexity on the other hand, PAI-1 can also directly bind to caspases. Intracellular PAI-1 can bind and inhibit caspase-3, promoting an anti-apoptotic effect. Inhibition of caspase-3 activity protects tumor cells from chemotherapy induced apoptosis (Schneider et al, 2008).
Given the diverse biological effects of PA1-1 in complex diseases, PAI-1 inhibition has been developed as a novel therapeutic concept. Pharmaceutical industry and academia developed molecules that can inhibit PAI-1 with the hope to favorably alter the course of endemic complex diseases such as atherosclerosis, cancer, Alzheimer disease, and aging. PAI-1 inhibitors cover a large group of novel therapeutics which include monoclonal antibodies, peptides, low molecular weight compounds, and chemical suppressors (Fortenberry 2013; Rouch et al. 2015). Several small molecule PAI-1 inhibitors using high throughput screening have recently been identified (Fortenberry 2013). As discussed in the structure of PAI-1 section, the reactive center loop has been the target of these inhibitors. The aim of the PAI-1 inhibitor is to induce a conformational change in the molecular structure of PAI-1 so that it cannot form 1:1 stoichiometric complexes with its target protease. By blocking the interaction of PAI-1 to bind plasminogen activators, PAI-1 is automatically converted into its latent form. One such example is tiplaxtinin. Tiplaxtinin is one indole oxoacetic acid PAI-1 inhibitor, PAI-039 (Elokdah et al. 2004). Its antithrombotic activity is being tested in animal models as a potential therapeutic agent in arterial thrombosis (Elokdah et al. 2004; Hennan et al. 2008). Several other small molecule inhibitors have been tested in preclinical studies. The scope and the space of the current review will not enable us to summarize the entire evidence on small molecule PAI-1 inhibitors. However, current evidence indicate that despite their good anti-PAI-1 activity in vitro, data are needed to further pursue the safety and long-term outcome with these agents. Moreover, one potential down side for small molecule inhibitors is that they do not interfere with vitronectin binding of PAI-1. Vitronectin binding is responsible in determining the stability of PAI-1. The small molecule inhibitors are limited in modifying the stability of PAI-1 (Gorlatova et al. 2007). PAI-1 stimulates angiogenesis through by antiprotease and vitronectin-binding properties.
Recently, a new class of nucleic acid molecules termed aptamers is receiving attention as potential therapeutic PAI-1 inhibitors. By definition nucleic acid aptamers are novel therapeutic agents with short RNA or DNA molecules. They can be designed to bind to their target protein with high affinity and specificity. Aptamers have been developed to bind RCL and vitronectin binding of PAI-1. They can potentially inhibit intracellular effects of PAI-1. The efficacy of these agents is being tested in cancer treatment (Pei et al. 2014; Fortenberry 2013).
PAI-1 is a multifaceted protein, involved in atherosclerosis, fibrosis, thrombosis, apoptosis, cell proliferation, and angiogenesis. It has dual roles in biological processes, for instance, in apoptosis as being anti- and pro-apoptotic, in cancer being pro- and antitumor effects. The vulnerability to change in activity is based on the dependence of PAI-1 effect on tpA and uPA, also binding to vitronectin. PAI-1 inserts its behavior to act as a molecular switch in cells. The source of PAI-1 affects biological activity as PAI-1 expressed by cancer cells behaves differently than PAI-1 expressed on normal cells on apoptosis (Lademann 2005; Balsara 2008). Despite a plethora of studies supporting PAI-1’s role in vascular biology and cancer, there is still controversy concerning the exact influence of PAI-1 inhibition on complex diseases. The development of PAI-1 inhibitors as therapeutics has gained much ground over the past decade. Future studies will confirm PAI-1 inhibitors as potential therapeutic agents in complex diseases. Collectively, experimental models illustrate that novel inhibitors are viable therapeutic agents and are currently being investigated.
Plasminogen activator inhibitor-1 (PAI-1) is a unique molecule that regulates of intra- and extravascular fibrinolysis. Structurally, PAI-1 is a serine protease inhibitor and plasminogen activators are its target proteinases. PAI-1 forms covalent complex with plasminogen activators (PA). The urokinase and tissue-type plasminogen activators (uPA and tPA) convert plasmin to plasmin and PAI-1 inhibits the formation of plasmin from plasminogen.
The unique structure makes PAI-1 a molecular switch in biology. In addition to a well-defined role in fibrinolysis, PAI-1 modulates several pathological processes such as vascular diseases, fibrosis, and cancer. Moreover, PAI-1 exerts various cellular effects independently of fibrinolysis. Recently the role in cancer has attracted full attention.
PAI-1 has dual roles in apoptosis and angiogenesis. Moreover, results from studies assessing the role of PAI-1 in apoptosis have suggested that PAI-1 can exert pathogenic or protective effects depending on the disease model or type of injury. As a result, inhibition of PAI-1 activity has emerged as a potential therapy in the two main complex disease groups such as vascular disease and cancer. In fact, PAI-1 appears to be at cross roads of the pathophysiology of these diseases and helps us to understand their complexity. Modulating PAI-1 activity by its inhibitors appears as a potential therapeutic target for cancer and vascular disease. Yet, the search for an ideal inhibitor of PAI-1 activity in biological systems is an ongoing effort. Over the past decades, many pharmacological studies have therefore been devoted to developing models for PAI-1 inhibitors. This article provides an overview of the role of PAI-1 as a novel therapeutic target.
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