Structure-Function Relationships of Plasminogen Activator Inhibitor-1 and Its Potential as a Therapeutic Agent
Jacqueline M. Cale and Daniel A. Lawrence
Affiliation: Department of Internal Medicine, Cardiovascular Research Center, University of Michigan, 1150 W Medical Center Dr, Ann Arbor MI 48109, USA.
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 lipoproteinreceptor 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-1s 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.
Keywords: human PAI-1 gene, top-emitting organic light emitting diodes, thin-film transistors, polymer light emitting diodes, electroluminescence
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