【Circulation】纤溶酶原激活抑制物—1在肾脏和心血管疾病中的作用
发布于 2009-04-15 · 浏览 994 · IP 河南河南
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The role of plasminogen activator inhibitor 1 in renal and cardiovascular diseases
纤溶酶原激活抑制物—1在肾脏和心血管疾病中的作用
Top of pageAbstractThe 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
Top of pageIntroduction
Plasminogen activator inhibitor 1 (PAI-1) is a 50 kDa single-chain glycoprotein (Figure 1) that acts as the primary physiological inhibitor of the two main mammalian plasminogen activators, tissue-type plasminogen activator (tPA) and urokinase-type plasminogen activator (uPA). PAI-1 inhibits tPA and uPA by forming an irreversible 1:1 molar complex with each molecule, which thereby blocks generation of plasmin and degradation of fibrin clots. The role of PAI-1 in the development of acute thrombotic disorders, including deep vein thrombosis and myocardial infarction, has been well recognized since the initial discovery of PAI-1 as a "fast inactivator" of plasminogen activator in 1977.1 The known functions of PAI-1 have, however, recently been extended to include roles in fibrotic disorders2, 3, 4 (atherosclerosis; renal and pulmonary fibrosis), metabolic disorders4, 5, 6 (obesity and type 2 diabetes), and cancer.4, 7 These recent inclusions are a result of the realization that plasmin has a broad spectrum of substrates other than fibrin, including inactive transforming growth factor 1 (TGF-1), matrix metalloproteinases (MMPs), and structural components of the extracellular matrix (ECM) such as type IV collagen, fibronectin, laminin, and proteoglycan.8, 9 Here, we briefly review the current understanding of the regulation of PAI-1 expression, the role of PAI-1 in renal and cardiovascular diseases, and the development of strategies to suppress PAI-1, including orally active small-molecule inhibitors.
全文请看 http://www.nature.com/nrneph/journal/v5/n4/full/nrneph.2009.15.html#abs
纤溶酶原激活抑制物—1在肾脏和心血管疾病中的作用
Top of pageAbstractThe 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
Top of pageIntroduction
Plasminogen activator inhibitor 1 (PAI-1) is a 50 kDa single-chain glycoprotein (Figure 1) that acts as the primary physiological inhibitor of the two main mammalian plasminogen activators, tissue-type plasminogen activator (tPA) and urokinase-type plasminogen activator (uPA). PAI-1 inhibits tPA and uPA by forming an irreversible 1:1 molar complex with each molecule, which thereby blocks generation of plasmin and degradation of fibrin clots. The role of PAI-1 in the development of acute thrombotic disorders, including deep vein thrombosis and myocardial infarction, has been well recognized since the initial discovery of PAI-1 as a "fast inactivator" of plasminogen activator in 1977.1 The known functions of PAI-1 have, however, recently been extended to include roles in fibrotic disorders2, 3, 4 (atherosclerosis; renal and pulmonary fibrosis), metabolic disorders4, 5, 6 (obesity and type 2 diabetes), and cancer.4, 7 These recent inclusions are a result of the realization that plasmin has a broad spectrum of substrates other than fibrin, including inactive transforming growth factor 1 (TGF-1), matrix metalloproteinases (MMPs), and structural components of the extracellular matrix (ECM) such as type IV collagen, fibronectin, laminin, and proteoglycan.8, 9 Here, we briefly review the current understanding of the regulation of PAI-1 expression, the role of PAI-1 in renal and cardiovascular diseases, and the development of strategies to suppress PAI-1, including orally active small-molecule inhibitors.
全文请看 http://www.nature.com/nrneph/journal/v5/n4/full/nrneph.2009.15.html#abs
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