Structure-function relationships of plasminogen activator inhibitor-1 and its potential as a therapeutic agent

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 PAM 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.