Editorial [Hot Topic: Plasminogen Activator Inhibitor-1 (Guest Editor: Daniel A. Lawrence)]
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.
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.
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.
Document Type: Research Article
Publication date: 01 September 2007
- Current Drug Targets aims to cover the latest and most outstanding developments on the medicinal chemistry and pharmacology of molecular drug targets e.g. disease specific proteins, receptors, enzymes, genes. Each issue of the journal will be devoted to a single timely topic, with series of in-depth reviews, written by leaders in the field, covering a range of current topics on drug targets. These issues will be organized and led by a guest editor who is a recognized expert in the overall topic. As the discovery, identification, characterisation and validation of novel human drug targets for drug discovery continues to grow; this journal will be essential reading for all pharmaceutical scientists involved in drug discovery and development.
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