Plasminogen activator inhibitor-1 (PAI-1) also known asendothelial plasminogen activator inhibitor (serpin E1) is aprotein that in humans is encoded by theSERPINE1gene. Elevated PAI-1 is a risk factor forthrombosis andatherosclerosis.[5]
The other PAI,plasminogen activator inhibitor-2 (PAI-2) is secreted by theplacenta and only present in significant amounts duringpregnancy. In addition,proteasenexin acts as an inhibitor of tPA and urokinase. PAI-1, however, is the main inhibitor of the plasminogen activators.
The PAI-1gene isSERPINE1, located onchromosome 7 (7q21.3-q22). There is a commonpolymorphism known as 4G/5G in the promoter region. The 5G allele is slightly less transcriptionally active than the 4G.
PAI-1's main function entails the inhibition ofurokinase plasminogen activator (uPA), an enzyme responsible for the cleavage ofplasminogen to formplasmin. 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.[6] Thus, PAI can be said to inhibit theserine proteases tPA and uPA/urokinase, and hence is an inhibitor offibrinolysis, 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 thebasal lamina.
Congenital deficiency of PAI-1 has been reported; as fibrinolysis is not suppressed adequately, it leads to ahemorrhagic diathesis (a tendency to hemorrhage).
PAI-1 is present in increased levels in various disease states (such as a number of forms ofcancer), as well as inobesity and themetabolic syndrome. It has been linked to the increased occurrence ofthrombosis in patients with these conditions.
In inflammatory conditions in whichfibrin is deposited in tissues, PAI-1 appears to play a significant role in the progression tofibrosis (pathological formation ofconnective tissue). Presumably, lower PAI levels would lead to less suppression of fibrinolysis and conversely a more rapid degradation of the fibrin.
Angiotensin II increases the synthesis of plasminogen activator inhibitor-1, so it accelerates the development ofatherosclerosis.
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