Inhibition of PAI-1: A New Anti-thrombotic Approach

Author(s): Qingyu Wu, Zuchun Zhao

Journal Name: Current Drug Targets - Cardiovascular & Hematological Disorders
Continued as Cardiovascular & Hematological Disorders-Drug Targets

Volume 2 , Issue 1 , 2002


Proteolytic degradation of fibrin (fibrinolysis) is mediated by plasminogen and its activators, tissue-type plasminogen activator (tPA1) and urokinase (uPA). Fibrinolysis is critical for preventing thrombus growth and restoring blood flow following thrombotic vascular occlusion. Plasminogen activator inhibitor-1 (PAI-1), a member of the serine protease inhibitor (serpin) superfamily, is the principal inhibitor of tPA and uPA in the fibrinolytic system. High levels of circulating PAI-1 are associated with a number of thrombotic diseases. In animal studies, transgenic mice overexpressing human PAI-1 develop spontaneous thrombosis, whereas PAI-1-deficient mice are more resistant to venous or arterial thrombosis. Furthermore, inhibition of PAI-1 activity prevents thrombus formation in animal models. The antithrombotic effects of PAI-1 inhibition are achieved by enhancing endogenous fibrinolytic activity without directly affecting blood coagulation and platelet function. Phenotypic analysis of PAI-1 deficiency in both human and mouse suggests that inhibition of PAI-1 will not lead to severe bleeding or other major adverse effects. Thus, PAI-1 inhibitors represent a new class of antithrombotic drugs with a possible wider therapeutic index than conventional antiplatelet and anticoagulant agents. This review summarizes the role of PAI-1 in thrombotic diseases and recent progress in the development of small molecule PAI-1 inhibitors.

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Article Details

Year: 2002
Page: [27 - 42]
Pages: 16
DOI: 10.2174/1568006023337727

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PDF: 37