Plasminogen activator inhibitor-1 Plasminogen activator inhibitor-1 also known as endothelial plasminogen activator inhibitor or serpin E1 is a protein that in humans is encoded by the SERPINE1 gene . Elevated PAI-1 is a risk factor for thrombosis and atherosclerosis PAI-1 is a serine protease inhibitor that functions as the principal inhibitor of tissue plasminogen activator and urokinase , the activators of plasminogen and hence fibrinolysis . It is a serine protease inhibitor protein . The other PAI, plasminogen activator inhibitor-2 is secreted by the placenta and only present in significant amounts during pregnancy . In addition, protease nexin acts as an inhibitor of tPA and urokinase. PAI-1, however, is the main inhibitor of the plasminogen activators .Genetics The PAI-1 gene is SERPINE1 , located on chromosome 7 . There is a common polymorphism known as 4G/5G in the promoter region . The 5G allele is slightly less transcriptionally active than the 4G.Function PAI-1's main function entails the inhibition of urokinase plasminogen activator , an enzyme responsible for the cleavage of plasminogen to form plasmin . Plasmin mediates the degradation of the extracellular matrix either by itself or in conjunction with matrix metalloproteinases . In this scenario, PAI-1 inhibits uPA via active site binding, preventing the formation of plasmin. Additional inhibition is mediated by PAI-1 binding to the uPA/uPA receptor complex, resulting in the latter's degradation. Thus, PAI can be said to inhibit the serine proteases tPA and uPA/urokinase, and hence is an inhibitor of fibrinolysis, the physiological process that degrades blood clots . In addition, PAI-1 inhibits the activity of matrix metalloproteinases, which play a crucial role in invasion of malignant cells through the basal lamina . PAI-1 is mainly produced by the endothelium , but is also secreted by other tissue types, such as adipose tissue .Role in disease Congenital deficiency of PAI-1 has been reported; as fibrinolysis is not suppressed adequately, it leads to a hemorrhagic diathesis . PAI-1 is present in increased levels in various disease states, as well as in obesity and the metabolic syndrome . It has been linked to the increased occurrence of thrombosis in patients with these conditions. In inflammatory conditions in which fibrin is deposited in tissues, PAI-1 appears to play a significant role in the progression to fibrosis . Presumably, lower PAI levels would lead to less suppression of fibrinolysis and conversely a more rapid degradation of the fibrin.Angiotensin II increases synthesis of plasminogen activator inhibitor-1, so it accelerates the development of atherosclerosis.Pharmacology Plasminogen activator inhibitor-1 has been shown to interact with ORM1 .
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