Current Drug Targets

ISSN: 1389-4501

Current Drug Targets
Volume 8, Number 9, September 2007

Contents

Plasminogen Activator Inhibitor-1
Guest Editor: Daniel A. Lawrence


Editorial Pp. 960-961


PAI-1 Antagonists: Predictable Indications and Unconventional Applications Pp. 962-970
D.E. Vaughan, B.M. De Taeye and M. Eren
[Abstract]


Structure-Function Relationships of Plasminogen Activator Inhibitor-1 and Its Potential as a Therapeutic Agent Pp. 971-981
J.M. Cale and D.A. Lawrence
[Abstract]


Targeting Plasminogen Activator Inhibitor-1: Role in Cell Signaling and the Biology of Domain-Specific Knock-in Mice Pp. 982-995
R.D. Balsara, Z. Xu and V.A. Ploplis
[Abstract]


Plasminogen Activator Inhibitor-1 in Vascular Thrombosis Pp. 996-1002
R.J. Westrick and D.T. Eitzman
[Abstract]


Plasminogen Activator Inhibitor-1 and Restenosis Pp. 1003-1006
N. Garg and W.P. Fay
[Abstract]


PAI-1 as a Target in Kidney Disease Pp. 1007-1015
Y. Huang and N.A. Noble
[Abstract]


The Plasminogen Activation System in Lung Disease Pp. 1016-1029
T.H. Sisson and R.H. Simon
[Abstract]


PAI-1 - A Potential Therapeutic Target in Cancer Pp. 1030-1041
P.A. Andreasen
[Abstract]




Abstracts

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Editorial

Recent advances in our understanding of complex disease phenotypes have suggested that intricate and often obscure interactions between genetic and environmental factors are critical for determining the spectrum of outcomes in “lifestyle” diseases such as atherosclerosis or type 2 diabetes mellitus. One molecule of interest that has been implicated in pathological processes associated with lifestyle diseases, including atherosclerosis, obesity, and insulin resistance, is plasminogen activator inhibitor-1 (PAI-1) (Fig. 1). In healthy individuals PAI-1 is present at very low concentrations in plasma; however, its expression in many cell types can be strongly up-regulated by stress, or injury, and by many different factors including endotoxins, cytokines and growth factors. PAI-1 also interacts with multiple physiologic processes including inflammation, and thrombosis/fibrinolysis. The plasminogen activator (PA) system is a limited proteinase cascade in which highly specific serine proteinase activate the zymogen plasminogen to the broad-specificity proteinase enzyme plasmin. There are two primary plasminogen activators in mammals, tissue-type PA (tPA) and urokinase-type PA (uPA). There are also cofactors and cell surface receptors that interact with the proteinases and/or their inhibitors. PAI-1 is the most important PAI, and high PAI-1 levels are associated with both acute diseases such as sepsis and myocardial infarction, and with chronic disorders including cancer, fibrosis and atherosclerosis. The association of PAI-1 with these syndromes has led to the proposal that PAI-1 may contribute directly to the pathology of disease, and recent mechanistic studies suggests that the role of PAI-1 in disease development is complex. PAI-1 can act through multiple pathways, including modulation of fibrinolysis through the regulation of PAs, or by influencing tissue remodeling through the direct regulation of cell migration. Thus, PAI-1 may represent a prototypical factor involved in the development of lifestyle diseases, and as such may be an important target candidate for pharmacological intervention in a wide variety of settings.



Fig. (1). Adapted from Yepes, M., Loskutoff, D.J., & Lawrence, D.A. Plasminogen Activator Inhibitor-1. In: Hemostasis and Thrombosis : Basic Principles & Clinical Practice, Fifth Edition, Colman, R.W et al. (Eds.) Lippincott Williams & Wilkins, Chapter 19, pg 365-380; 2006.

In this issue of Current Drug Targets eight reviews focus on the role of PAI-1 in disease and on specific ways to target PAI-1. Topics include PAI-1 as a potential target in vascular diseases such as thrombosis and restenosis, in fibrotic renal and lung disease, and in cancer. Specific approaches for targeting PAI-1 are also discussed such as pharmacologic inhibitors of PAI-1 expression, direct small molecule antagonists of PAI-1 activity, and recombinant dominant negative PAI-1 decoy molecules.

In the first article of this issue Vaughan and colleagues (pages x-y) present a general introduction of the role of PAI-1 in a wide variety of diseases and discuss the use of small molecule PAI-1 antagonists. Their overview provides a context for the other articles in this issue, and demonstrates the many disease processes where PAI-1 is thought to play a critical role. This is followed by a general review of PAI-1 structure and function and a discussion of the use of PAI-1 itself as a potential therapeutic protein including the design and use of dominant negative PAI-1 decoy molecules (pages x-y). Balsara et al. (pages x-y) then probe the regulation of PAI-1 expression and discuss targeting these pathways. This is followed by two articles examining the role of PAI-1 in vascular disease. First, Westrick and Eitzman discuss the role of PAI-1 in vascular thrombosis (pages x-y), and this is followed by Garg and Fay’s examination of PAI-1 in vascular restenosis (pages x-y). The next two articles discuss the promising results from studies targeting PAI-1 in fibrotic diseases. On pages x-y Huang and Noble discuss PAI-1 as a target in kidney fibrosis and this is followed by Sisson and Simon’s examination of the PA-system in lung disease (pages x-y). Finally, Andreasen provides a comprehensive review of PAI-1 in cancer biology (pages x-y). Together, these papers provide a compelling case for the further understanding of PAI-1’s role in disease and for the development of strategies that target PAI-1 in a variety of diseases.


Daniel A. Lawrence


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PAI-1 Antagonists: Predictable Indications and Unconventional Applications
D.E. Vaughan, B.M. De Taeye and M. Eren

At present, thrombolytic agents represent the only direct way of augmenting fibrinolytic activity in humans. While these agents are proven to be efficacious in the treatment of acute thrombotic events, they are not a viable option for long-term administration. There are numerous drugs available that indirectly to increase fibrinolytic activity by reducing plasma levels of plasminogen activator inhibitor-1 (PAI-1), including ACE inhibitors, insulin-sensitizing agents, and hormone replacement therapy in women. At present, efforts are underway to develop and test synthetic, selective PAI-1 antagonists. The potential applications of PAI-1 antagonists include thrombotic disorders (arterial and venous), amyloidosis, obesity, polycystic ovarian syndrome, and perhaps even type 2 diabetes mellitus. The availability of specific PAI-1 antagonists promises to expand the limits of understanding the role the fibrinolytic system plays in human disease and break through the current confines of therapeutic options that can effectively restore and augment the activity of the fibrinolytic system.


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Structure-Function Relationships of Plasminogen Activator Inhibitor-1 and Its Potential as a Therapeutic Agent
J.M. Cale and D.A. Lawrence

Plasminogen activator inhibitor-1 (PAI-1) is the primary inhibitor of tissue-type and urokinase-type plasminogen activators (tPA and uPA, respectively). PAI-1 also interacts with non-proteinase targets such as vitronectin, heparin, and several endocytic receptors of the low-density lipoprotein-receptor family, including the low-density lipoprotein-receptor related protein (LRP) and the very low-density lipoprotein receptor (VLDLr). PAI-1 is a multifunctional protein that is not only a physiologic regulator of fibrinolysis and cell migration but is also associated with several acute and chronic pathologic conditions. PAI-1 is involved in the pathophysiology of renal, pulmonary, cardiovascular, and metabolic diseases, and in vitro experiments and animal studies have elucidated PAI-1’s contribution to the physiology or pathology of some of these conditions. PAI-1 is normally present at low levels in plasma, but acute and chronic diseases are strongly associated with increased PAI-1 expression and release. At sites of vascular injury and inflammation, local PAI-1 levels are even higher, due to its concentration in extracellular matrix through association with vitronectin. Elevated local or systemic PAI-1 is not only a marker of disease; it can also exacerbate pathologic conditions. Thus, interventions that directly target PAI-1 may be useful for the treatment of a number of chronic and acute disorders. Typically, such interventional strategies would involve the identification of small molecule inhibitors of PAI-1, and several recent reviews have covered this topic. However, it may also be possible or even potentially advantageous, to exploit the diverse functional interactions of PAI-1 to create highly specific and targeted therapeutic agents based on the PAI-1 protein itself. To understand how PAI-1 could be developed as a therapeutic agent, it is first necessary to discuss its structural and functional characteristics in depth.


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Targeting Plasminogen Activator Inhibitor-1: Role in Cell Signaling and the Biology of Domain-Specific Knock-in Mice
R.D. Balsara, Z. Xu and V.A. Ploplis

It is well documented that elevated levels of PAI-1 in plasma can decrease the fibrinolytic activity in blood with an associated increased risk of thrombus formation. A diverse range of molecules including bacterial lipopolysaccharide (LPS), the inflammatory mediators tumor necrosis factor α (TNFα) and interleukins, thrombin, transforming growth factor-β (TGF-β), and hormones regulate the synthesis of plasma PAI-1. Therefore, it is of clinical importance to restore the fibrinolytic balance. For a drug to be effective in controlling the synthesis of PAI-1, sufficient insight into the signal transduction pathways that control its regulation is desirable, which could serve as logical targets for the development of pharmaceuticals. Some key signaling pathways have been identified with the aid of pharmacological inhibitors, involved in the up-regulation of PAI-1 in context with several diseases, including obesity, insulin resistance, diabetic nephropathy, glomulonephritis, and pulmonary fibrosis. Furthermore, independent of its inhibitory activity PAI-1 mediates interactions with vitronectin (VN) and low density lipoprotein receptor-related protein (LRP) which modifies basic cell behaviors of proliferation, migration, and attachment. Intriguingly, it has been shown that both anti-fibrinolytic and non-fibrinolytic-related functions of PAI-1 may have overlapping roles in many diseases that are poorly understood. Tailoring knock-in mice with site-specific alterations that diminish the inhibitory activity, VN-binding, and LRP-binding activity of PAI-1 are useful tools for manipulation of biochemical properties, in vivo, and evaluating therapeutics.


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Plasminogen Activator Inhibitor-1 in Vascular Thrombosis
R.J. Westrick and D.T. Eitzman

Thrombotic complications of vascular disease constitute the leading cause of morbidity and mortality in much of the developed world. Current drug therapies available to treat the thrombotic component of arterial and venous vascular complications remain limited. Novel safe and effective treatment strategies to reduce formation of occlusive thrombosis will likely have a major impact on reducing the economic burden of vascular disease on the healthcare system. Enhancing endogenous fibrinolysis by targeting plasminogen activator inhibitor–1 (PAI-1), the primary inhibitor of circulating plasminogen activators, has been shown to be effective in markedly attenuating the formation of arterial and venous occlusive thrombosis in animal models. In addition, animal and human studies of PAI-1 deficiency indicate that spontaneous bleeding complications associated with even complete PAI-1 deficiency would be rare. Patients most likely to benefit from PAI-1 inhibition would be those at high risk for vascular events where PAI-1 is elevated, such as is observed in obesity, diabetes and the metabolic syndrome. Since obesity and metabolic syndrome are now epidemic, and will likely have a major adverse impact on vascular thrombotic events, it may be time to test the clinical effectiveness of PAI-1 inhibition in a patient population at high risk for vascular thrombosis.


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Plasminogen Activator Inhibitor-1 and Restenosis
N. Garg and W.P. Fay

Despite the introduction of drug-eluting stents restenosis remains an important clinical problem. In this review we examine the role of plasminogen activator inhibitor-1 (PAI-1) in controlling restenosis after balloon angioplasty and stent implantation.


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PAI-1 as a Target in Kidney Disease
Y. Huang and N.A. Noble

Fibrotic renal diseases represent a major health care problem because of their prevalence and the fact that available therapies merely slow, but do not halt progression to renal failure. New therapies to further slow or stop the progression to end stage of renal disease (ESRD) are urgently needed. PAI-1 has emerged as a powerful fibrogenic molecule in kidney disease and its overexpression has effects beyond its role in regulating the fibrinolytic system. PAI-1’s ability to inhibit plasmin-dependent extracellular matrix turnover, to stimulate infiltration of macrophages and myofibroblasts and to signal directly to regulate transforming growth factor-beta 1 expression, provide possible mechanistic pathways involved in progression of chronic kidney disease. Blockade of PAI-1 represents a new and promising therapeutic approach that may help combat the current epidemic in chronic kidney disease.


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The Plasminogen Activation System in Lung Disease
T.H. Sisson and R.H. Simon

The importance of the plasminogen activator (PA) system in multiple pulmonary disorders has become increasingly apparent as methods to analyze its components have improved. Early investigations discovered that the pulmonary alveolar space is normally a pro-fibrinolytic environment that is diminished in a variety of lung diseases. Interest in these observations was greatly increased when animal experiments revealed that manipulations of the PA system significantly modulated the tissue fibrosis that follows many types of lung injury. In particular, enhancement of PA activity was found to consistently decrease the extent of scarring induced by lung damage. Based upon these early observations, it was hypothesized that fibrin was necessary for the pathogenesis of lung fibrosis, and that an increase in PA activity would reduce collagen accumulation by accelerating the clearance of fibrin from the provisional matrix. However, as is often the case with simple hypotheses, subsequent studies revealed that the actual role of the PA system in pulmonary disease is much more complex. Possible mechanisms beyond fibrinolysis include degradation of other matrix proteins, activation of protease cascades including those involving matrix metalloproteinases, activation and release of growth factors from sites of production and sequestration, and modulation of cell adhesion and motility. In each of these processes, the serpin plasminogen activator inhibitor-1 (PAI-1) plays a central role. For these reasons, it has become apparent that PAI-1 presents an attractive target to influence multiple disease processes within the lung, particularly those that lead to lung fibrosis.


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PAI-1 - A Potential Therapeutic Target in Cancer
P.A. Andreasen

Beginning in the early 90es, evidence has been accumulating that a high level of plasminogen activator inhibitor-1 (PAI-1) protein in extracts of human primary malignant tumours is one of the most informative biochemical markers of a poor prognosis in several human cancer types. This observation has given the impetus to numerous studies of the role of PAI-1 in tumour growth, invasion, and metastasis. Recent mapping of cell types expressing PAI-1 in human tumours and studies with tumours growing on mice with targeted disruption of the PAI-1 gene have given results consistent with the idea that PAI-1 expressed by stromal fibroblasts and endothelial cells promotes tumour growth and spread. PAI-1 expressed by these cells therefore seems to be a potential therapeutic target in cancer. Confusingly, however, PAI-1 is also expressed by other cell types in tumours, and in some cancer types, the predominant PAI-1-expressing cells are the malignant epithelial cells themselves. Adding to the complexity is the fact that PAI-1 is not only a plasminogen activator inhibitor, but also engages in other molecular interactions, i.e., binds the extracellular matrix protein vitronectin and endocytosis receptors of the low density lipoprotein receptor family. Further progress towards the utilisation of PAI-1 as a therapeutic target in cancer will depend on understanding the role of PAI-1 expressed by different cell types in tumours and on development of compounds inhibiting separately each molecular interaction of PAI-1. The eventual use of PAI-1 as a therapeutic target will depend on mapping PAI-1 levels and PAI-1 expressing cell types in tumours of individual patients.