Abstract
The 50 kDa glycoprotein plasminogen activator inhibitor 1 (PAI-1) is the major physiological inhibitor of tissue-type and urokinase-type plasminogen activator. These two molecules convert inactive plasminogen into its fibrin-degrading form, plasmin. Plasma and tissue concentrations of PAI-1 are extremely low under normal circumstances but increase under pathologic conditions. This increase is mediated by many factors, including reactive oxygen species. Increased PAI-1 activity is associated with an increased risk of ischemic cardiovascular events and tissue fibrosis. Whereas the antifibrinolytic property of PAI-1 derives mainly from its inhibition of serine proteases, its profibrotic actions seem to derive from a capacity to stimulate interstitial macrophage recruitment and increase transcription of profibrotic genes, as well as from inhibition of serine proteases. Despite studies in mice that lack or overexpress PAI-1, the biological effects of this molecule in humans remain incompletely understood because of the complexity of the PAI-1-plasminogen- activator-plasmin system. The cardioprotective and renoprotective properties of some currently available drugs might be attributable in part to inhibition of PAI-1. The development of an orally active, high-affinity PAI-1 inhibitor will provide a potentially important pharmacological tool for further investigation of the role of PAI-1 and might offer a novel therapeutic strategy in renal and cardiovascular diseases.
| Original language | English |
|---|---|
| Pages (from-to) | 203-211 |
| Number of pages | 9 |
| Journal | Nature Reviews Nephrology |
| Volume | 5 |
| Issue number | 4 |
| DOIs | |
| State | Published - Apr 2009 |
Bibliographical note
Funding Information:This work was supported in part by grants from the Korea research Foundation (#e00014), the Korea science and engineering Foundation (#rOi‑2006‑000‑ 10829‑0 and #r15‑2006‑020), and the second stage of Brain Korea 21 Project.
