Figure 1. Plasminogen activator inhibitor-1 signaling pathway.
Plasminogen activator inhibitor-1 overview
Plasminogen activator inhibitor-1 (PAI-1) is a member of the fibrinolytic system plasminogen activator (PA), such as tissue plasminogen activator (t-PA) and urokinase-type fiber, the main physiological inhibitor of lysogen activator (u-PA) is the major regulator of fibrinolytic activity. Studies have shown that PAI-1 has a wide range of effects in various pathological processes such as cardiovascular diseases and tumors. PAI-1 has broad research prospects as a new pharmacological target, and the development of new and highly effective PAI-1 inhibitors has an important research value.
Plasminogen activator inhibitor-1 family
Plasminogen activator inhibitor (PAI) was first discovered in pregnant women's plasma by Brakman and Astrup in 1963 and has been discovered by other investigators. It has been found that human PAI includes PAI-1, PAI-2, PAI-3 and PAI-4. Among the four PAIs, PAI-1 has 99% activity and plays a major role. PAI-1 is widely distributed in the body's vascular endothelial cells, smooth muscle cells, liver cells, fat cells, macrophages, neutrophils, mesangial cells, platelets and some malignant cells. PAI-1 in plasma is mainly produced by vascular endothelial cells and hepatocytes. PAI-1 is extremely unstable in vitro and in vivo, and its half-life is about 20 min, mainly because its active center of methionine is easily oxidized and PAI-1 is swallowed by binding to t-PA or u-PA to form a complex. There are two main forms of PAI-1 in plasma, one active, called activated PAI-1, and the other inactive, called latent PAI-1. The two forms of PAI-1 have the same molecular weight and immunoreactivity but differ in their configuration. The active PAI-1 can be stabilized and kept active by binding to a cellulose-binding protein.
Plasminogen activator inhibitor-1 signaling pathway
Plasminogen activator inhibitor-1 signaling pathway cascade
Due to the diversity of PAI-1 functions, the PAI-1 cascade can be described according to different functions: Tumor: Infiltration and metastasis of tumor cells is an extremely complex process, accompanied by extracellular matrix and basement membrane components. U-PA plays an important role in promoting tumor invasion and metastasis. U-PA can convert plasminogen into plasmin, degrade the extracellular matrix of normal tissues around tumor cells and collagen components in basement membrane, destroying normal tissues. The barrier function of the matrix promotes tumor invasion and metastasis. As a specific inhibitor of u-PA, PAI-1 has also attracted attention to the tumor, but its role in tumor development remains to be further studied. Studies have shown that PAI-1 can form a complex with u-PA, leading to the inactivation of u-PA, so that the tumor cell matrix is not dissolved by u-PA-mediated protein, preventing the tumor tissue itself from being destroyed, which is beneficial to tumor cells localize, grow and increase their invasiveness. The expression of PAI-1 in endothelial cells is high, which can prevent the extracellular matrix from being degraded during angiogenesis and contribute to the formation of intravascular blood vessels. PAI-1 and u-PA levels were detected in a variety of tumor tissues such as liver cancer, lung cancer, breast cancer, colon cancer, etc., especially in the tumor cells differentiation, invasiveness and metastasis. The cases are more prominent, and the level of PAI-1 is closely related to the prognosis. Baker and Leaper found that PAI-1 transcription levels were nearly 10-fold higher in colon cancer epithelial tissues compared with normal tissues, and u-PA was positively correlated with PAI-1 protein expression.
PAI-1 modulates migration through cell surface receptors. PAI-1 binding to LRP1, in a non-uPA/uPAR-dependent manner, triggers Jak/Stat1 signaling events that culminate in enhanced cell migration (left). It is unclear whether this process requires PAI-1 interaction with the ECM. PAI-1 binding to uPA/uPAR results in the internalization of the PAI-1/uPA/uPAR complexes in an LRP1-dependent manner (middle). PAI-1 binding to uPA/uPAR can also trigger the detachment of cell surface integrins from their ECM ligands and subsequent internalization in an LRP1-uPA/uPAR-dependent manner.
Relationship with disease
Many studies have shown that PAI-1 plays an important role in the occurrence, development and metastasis of tumors, and this effect is very complicated, so the specific mechanisms and treatment strategies remain to be further studied.
The specific mechanism is preceded described: the formation of thrombus further increases the activity of PAI-1, accelerates the formation of fibrin, deposits it in the body, especially on the blood vessel wall, stimulates the proliferation and migration of vascular smooth muscle cells (SMC), and induces low density lipoprotein combined with SMC, deposited in the extracellular matrix, promotes the formation of fatty streaks and atherosclerotic plaques, thickens the vascular basement membrane, stiffens the blood vessel wall, and accelerates the progression of atherosclerosis.
Lize B, Marijke P, Miet P, et al. Active PAI-1 as marker for venous thromboembolism: case-control study using a comprehensive panel of PAI-1 and TAFI assays. Thrombosis Research. 2014, 134(5):1097-1102.
Natesirinilkul R, Sasanakul W, Chuansumrit A, et al. Global fibrinolytic activity, PAI-1 level, and 4G/5G polymorphism in Thai children with arterial ischemic stroke. Journal of Stroke & Cerebrovascular Diseases. 2014, 23(10):2566-2572.
Thapa B, Kim Y H, Kwon H J, et al. The LRP1-independent mechanism of PAI-1-induced migration in CpG-ODN activated macrophages. International Journal of Biochemistry & Cell Biology. 2014, 49(4):17-25.
Jankun J, Skrzypczak-Jankun E. Plasminogen activator inhibitor with very long half-life (VLHL PAI-1) can reduce bleeding in PAI-1-deficient patients. Cardiovascular & Haematological Disorders - Drug Targets. Formerly Current D. 2013, 13(2)
Chen F, Zhang G, Hong Z, et al. Design, synthesis, and SAR of embelin analogues as the inhibitors of PAI-1 (plasminogen activator inhibitor-1). Bioorganic & Medicinal Chemistry Letters. 2014, 24(10):2379-2382.
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