“Plasminogen activator inhibitor-1”的意思、由来-开放百科全书

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).

The other PAI, plasminogen activator inhibitor-2 (PAI-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 (7q21.3-q22). 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 (uPA), 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.^[2] 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 (cells lining blood vessels), 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 (a tendency to hemorrhage).

PAI-1 is present in increased levels in various disease states (such as a number of forms of cancer), 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 (pathological formation of connective tissue). 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

Interactions

References

1. ^{{cite journal | vauthors = Vaughan DE | title = PAI-1 and atherothrombosis | journal = Journal of Thrombosis and Haemostasis | volume = 3 | issue = 8 | pages = 1879–83 | date = August 2005 | pmid = 16102055 | doi = 10.1111/j.1538-7836.2005.01420.x }}
2. ^{{cite journal | vauthors = Carter JC, Church FC | title = Obesity and breast cancer: the roles of peroxisome proliferator-activated receptor-γ and plasminogen activator inhibitor-1 | journal = PPAR Research | volume = 2009 | pages = 345320 | date = 2009 | pmid = 19672469 | doi = 10.1155/2009/345320 | pmc=2723729}}
3. ^{{cite journal | vauthors = Elokdah H, Abou-Gharbia M, Hennan JK, McFarlane G, Mugford CP, Krishnamurthy G, Crandall DL | title = Tiplaxtinin, a novel, orally efficacious inhibitor of plasminogen activator inhibitor-1: design, synthesis, and preclinical characterization | journal = Journal of Medicinal Chemistry | volume = 47 | issue = 14 | pages = 3491–4 | date = July 2004 | pmid = 15214776 | doi = 10.1021/jm049766q | citeseerx = 10.1.1.661.4972 }}
4. ^{{cite journal | vauthors = Pautus S, Alami M, Adam F, Bernadat G, Lawrence DA, De Carvalho A, Ferry G, Rupin A, Hamze A, Champy P, Bonneau N, Gloanec P, Peglion JL, Brion JD, Bianchini EP, Borgel D | title = Characterization of the Annonaceous acetogenin, annonacinone, a natural product inhibitor of plasminogen activator inhibitor-1 | journal = Scientific Reports | volume = 6 | issue = | pages = 36462 | year = 2016 | pmid = 27876785 | pmc = 5120274 | doi = 10.1038/srep36462 }}
5. ^{{cite journal | vauthors = Boncela J, Papiewska I, Fijalkowska I, Walkowiak B, Cierniewski CS | title = Acute phase protein alpha 1-acid glycoprotein interacts with plasminogen activator inhibitor type 1 and stabilizes its inhibitory activity | journal = The Journal of Biological Chemistry | volume = 276 | issue = 38 | pages = 35305–11 | date = September 2001 | pmid = 11418606 | doi = 10.1074/jbc.M104028200 }}