Plasminogen Activator Inhibitors

Tissue plasminogen activator (tPA) and urokinase plasminogen activator (uPA) and their inhibitor, plasminogen activator inhibitor 1 (PAI-1) are involved in the regulation of tissue morphogenesis and differentiation. Plasminogen activator-mediated extracellular matrix degradation plays an important role in the development of tumors and tumor metastasis. Over-expressed tPA and uPA systems are reported in patients with aggressive metastasizing tumors. Hence, inhibition of plasminogen activation is an important pharmacological target for blocking metastasis and reducing primary tumor growth.

tPA is a serine protease that converts plasminogen to plasmin and can trigger the degradation of extracellular matrix proteins. The tPA/plasmin proteolytic system has been implicated in both physiological and pathological processes. In the brain tPA promotes events associated with synaptic plasticity such as motor learning and long-term potentiation. Under non-inflammatory conditions it also contributes to excitotoxic neuronal death. Outside the nervous system tPA is mainly found in the blood, where it functions as a thrombolytic enzyme and prevents excess fibrin accumulation in vessels.

PAI-1, a serine proteinase inhibitor, is a 50 kDa glycoprotein that acts as an important physiological inhibitor of tPA and uPA. It plays a crucial role in the regulation of vascular thrombosis, tumor invasion, neovascularization, and inflammation. Higher plasma levels of PAI-1 are correlated with an increased risk for cardiovascular diseases.

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