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 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.
Cale
Jacqueline M
JM
Department of Internal Medicine, Cardiovascular Research Center, University of Michigan, 1150 W Medical Center Dr, Ann Arbor, MI 48109, USA.
Lawrence
Daniel A
DA
D000818:Animals; D006801:Humans; D009154:Mutation; D017395:Plasminogen Activator Inhibitor 1 / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D017433:Protein Structure, Secondary; D015842:Serine Proteinase Inhibitors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D013329:Structure-Activity Relationship; D014158:Transcription, Genetic
D017395:Plasminogen Activator Inhibitor 1; D015842:Serine Proteinase Inhibitors