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The role of plasminogen activator inhibitor 1 in renal and cardiovascular diseases

Nature Reviews Nephrology volume 5, pages 203–211 (2009)Cite this article

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.

Key Points

  • Plasminogen activator inhibitor 1 (PAI-1) is an antifibrinolytic and profibrotic protein; its antifibrinolytic properties derive mainly from inhibition of serine protease activity

  • The mechanisms of PAI-1's profibrotic action are complex; in addition to inhibiting serine proteases, PAI-1 might promote interstitial macrophage recruitment and exert direct cellular effects through binding the urokinase-type plasminogen activator receptor

  • Improved understanding of the signaling pathways involved in PAI-1-induced gene transcription will aid the development of novel therapeutic strategies for ischemic and fibrotic diseases

  • Several currently available renoprotective drugs have PAI-1 inhibitory activity; development of an orally active, specific PAI-1 inhibitor could provide a pharmacological tool for investigating the role of PAI-1 and might have therapeutic potential

  • Reactive oxygen species have a role in the upregulation of PAI-1; therefore, the efficacy of antioxidants in the treatment and prevention of ischemic cardiovascular disease and renal fibrosis warrants investigation

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Figure 1: Three-dimensional structure of active human plasminogen activator inhibitor 1.
Figure 2: Potential mechanisms of plasminogen activator inhibitor 1 upregulation by transforming growth factor β1.
Figure 3: Proposed roles of plasminogen activator inhibitor 1 in vascular disease and fibrosis.

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Acknowledgements

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.

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  1. College of Pharmacy and the Division of Life & Pharmaceutical Sciences, Ewha Womans University, Seoul, South Korea

    Hunjoo Ha & Eun Y. Oh

  2. Soon Chun Hyang University College of Medicine, Kim's Clinic and Dialysis Unit, Miryang, South Korea

    Hi B. Lee

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Ha, H., Oh, E. & Lee, H. The role of plasminogen activator inhibitor 1 in renal and cardiovascular diseases. Nat Rev Nephrol 5, 203–211 (2009). https://doi.org/10.1038/nrneph.2009.15

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