Plasminogen activator inhibitor-1 (PAI-1) also known as endothelial plasminogen activator inhibitor or serpin E1 is a protein that in humans is encoded by the SERPINE1 gene. PAI-1 is a serine protease inhibitor (serpin) that functions as the principal inhibitor of tissue plasminogen activator (tPA) and urokinase (uPA), the activators of plasminogen and hence fibrinolysis (the physiological breakdown of blood clots). It is a serine protease inhibitor (serpin) protein (SERPINE1).
An Overview of PAI-1
Plasminogen activator inhibitor-1 (PAI-1) is a primary inhibitor of tissue-type plasminogen activator (tPA) and urokinase-type plasminogen activator (uPA), and is functionally served to suppress tissue and plasma fibrinolysis. PAI-1 is a single-chain glycoprotein consisting of 357 amino acids. It is a main inhibitor of plasminogen activator and can inhibit the transformation of plasminogen into plasminogen. PAI-1 seems to play a pivotal role in tumor growth and may represent a potential therapeutic target for bladder cancer. It has been confirmed that transforming growth factor beta (TGF- β) and angiotensin I can up-regulate the expression of PAI-1 in kidney.
Inhibition of PAI-1
The inhibitors currently being developed for PAI-1 are as follows: Tiplaxtinin, TM5441, TM5275 sodium, Loureirin B. Tiplaxtinin is an effective oral selective PAI-1 inhibitor with an IC50 of 2.7 μm. The IC50 value of TM5441 ranges from 9.7 μM to 60.3 μM. It could inhibit many tumor cell lines. The IC50 value of TM5275 sodium is 6.95 μm. Loureirin B is a flavonoid isolated from Ye Long's blood tree. Its IC50 value is 26.10 μM. Loureirin B has anti-diabetic effect.
PAI-1 and diseases
PAI-1 is not expressed in normal kidney, but it is overexpressed in diabetic nephropathy. It has been found that the elevated level of PAI-1 is related to the development of diabetes, but not to the change of fibrinogen. The level of PAI-1 increases with the increase of blood glucose and the development of diabetes mellitus. The increase of PAI-1 level mediates diabetic vascular complications, which proves that the increase of PAI-1 level promotes the occurrence and development of diabetic nephropathy. Vascular endothelial injury and dysfunction lead to the synthesis and release of t-PA and decrease the increase of PAI-1 synthesis. The decrease of fibrinolytic activity leads to the excessive aggregation of fibrin clearance disorder, which exacerbates the injury of vascular endothelial cells. This leads to a vicious circle between fibrinolysis and progression of diabetic nephropathy.