Plasminogen activator inhibitor-1 explained

Plasminogen activator inhibitor-1 (PAI-1) also known as endothelial plasminogen activator inhibitor (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.^[1]

PAI-1 is a serine protease inhibitor (serpin) that functions as the principal inhibitor of tissue-type 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.

PAI-1 can induce cellular senescence.^[3] PAI-1 can also be a component of the senescence-associated secretory phenotype (SASP).^[4]

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 the synthesis of plasminogen activator inhibitor-1, so it accelerates the development of atherosclerosis.

Pharmacology

• Tiplaxtinin (PAI-039) is a small molecule inhibitor that is being studied for use in the attenuation of remodeling of blood vessels, a result of arterial hypertension and activation of the renin–angiotensin system.^[5]
• Annonacinone is a naturally occurring PAI-1 inhibitor found in plants of the Annonaceae family.^[6]
• TM5441 is another small molecule PAI-1 inhibitor used in research.^[7]

Interactions

Plasminogen activator inhibitor-1 has been shown to interact with ORM1.^[8]

Further reading

• Mimuro J . [Type 1 plasminogen activator inhibitor: its role in biological reactions] . [Rinsho Ketsueki] the Japanese Journal of Clinical Hematology . 32 . 5 . 487–489 . May 1991 . 1870265 .
• Binder BR, Christ G, Gruber F, Grubic N, Hufnagl P, Krebs M, Mihaly J, Prager GW . 6 . Plasminogen activator inhibitor 1: physiological and pathophysiological roles . News in Physiological Sciences . 17 . 2 . 56–61 . April 2002 . 11909993 . 10.1152/nips.01369.2001 . 21356023 .
• Eddy AA . Plasminogen activator inhibitor-1 and the kidney . American Journal of Physiology. Renal Physiology . 283 . 2 . F209–F220 . August 2002 . 12110504 . 10.1152/ajprenal.00032.2002 .
• Wang J, Li J, Liu Q . Association between platelet activation and fibrinolysis in acute stroke patients . Neuroscience Letters . 384 . 3 . 305–309 . August 2005 . 15916851 . 10.1016/j.neulet.2005.04.090 . 22979258 .
• Schroeck F, Arroyo de Prada N, Sperl S, Schmitt M, Viktor M . Interaction of plasminogen activator inhibitor type-1 (PAI-1) with vitronectin (Vn): mapping the binding sites on PAI-1 and Vn . Biological Chemistry . 383 . 7–8 . 1143–1149 . 2003 . 12437099 . 10.1515/BC.2002.125 . 37813055 .
• Gils A, Declerck PJ . The structural basis for the pathophysiological relevance of PAI-I in cardiovascular diseases and the development of potential PAI-I inhibitors . Thrombosis and Haemostasis . 91 . 3 . 425–437 . March 2004 . 14983217 . 10.1160/TH03-12-0764 . 3898268 .
• Durand MK, Bødker JS, Christensen A, Dupont DM, Hansen M, Jensen JK, Kjelgaard S, Mathiasen L, Pedersen KE, Skeldal S, Wind T, Andreasen PA . 6 . Plasminogen activator inhibitor-I and tumour growth, invasion, and metastasis . Thrombosis and Haemostasis . 91 . 3 . 438–449 . March 2004 . 14983218 . 10.1160/TH03-12-0784 . 3898546 .
• Harbeck N, Kates RE, Gauger K, Willems A, Kiechle M, Magdolen V, Schmitt M . Urokinase-type plasminogen activator (uPA) and its inhibitor PAI-I: novel tumor-derived factors with a high prognostic and predictive impact in breast cancer . Thrombosis and Haemostasis . 91 . 3 . 450–456 . March 2004 . 14983219 . 10.1160/TH03-12-0798 . 19904733 .
• Hertig A, Rondeau E . Plasminogen activator inhibitor type 1: the two faces of the same coin . Current Opinion in Nephrology and Hypertension . 13 . 1 . 39–44 . January 2004 . 15090858 . 10.1097/00041552-200401000-00006 . 30785986 .
• Hoekstra T, Geleijnse JM, Schouten EG, Kluft C . Plasminogen activator inhibitor-type 1: its plasma determinants and relation with cardiovascular risk . Thrombosis and Haemostasis . 91 . 5 . 861–872 . May 2004 . 15116245 . 10.1160/TH03-08-0546 . 21576955 .
• Lijnen HR . Pleiotropic functions of plasminogen activator inhibitor-1 . Journal of Thrombosis and Haemostasis . 3 . 1 . 35–45 . January 2005 . 15634264 . 10.1111/j.1538-7836.2004.00827.x . 37085650 . free .
• De Taeye B, Smith LH, Vaughan DE . Plasminogen activator inhibitor-1: a common denominator in obesity, diabetes and cardiovascular disease . Current Opinion in Pharmacology . 5 . 2 . 149–154 . April 2005 . 15780823 . 10.1016/j.coph.2005.01.007 .
• Dellas C, Loskutoff DJ . Historical analysis of PAI-1 from its discovery to its potential role in cell motility and disease . Thrombosis and Haemostasis . 93 . 4 . 631–640 . April 2005 . 15841306 . 10.1160/TH05-01-0033 . 8937106 .
• Könsgen D, Mustea A, Lichtenegger W, Sehouli J . [Role of PAI-1 in gynaecological malignancies] . Zentralblatt für Gynakologie . 127 . 3 . 125–131 . June 2005 . 15915389 . 10.1055/s-2005-836407 . 260353538 .
• Hermans PW, Hazelzet JA . Plasminogen activator inhibitor type 1 gene polymorphism and sepsis . Clinical Infectious Diseases . 41 . Suppl 7 . S453–S458 . November 2005 . 16237647 . 10.1086/431996 . free .
• Alessi MC, Poggi M, Juhan-Vague I . Plasminogen activator inhibitor-1, adipose tissue and insulin resistance . Current Opinion in Lipidology . 18 . 3 . 240–245 . June 2007 . 17495595 . 10.1097/MOL.0b013e32814e6d29 . 27667588 .

External links

• The MEROPS online database for peptidases and their inhibitors: I04.020

Notes and References

1. Vaughan DE . PAI-1 and atherothrombosis . Journal of Thrombosis and Haemostasis . 3 . 8 . 1879–1883 . August 2005 . 16102055 . 10.1111/j.1538-7836.2005.01420.x . 6651339 . free .
2. Carter JC, Church FC . Obesity and breast cancer: the roles of peroxisome proliferator-activated receptor-γ and plasminogen activator inhibitor-1 . PPAR Research . 2009 . 345320 . 2009 . 19672469 . 2723729 . 10.1155/2009/345320 . free .
3. Zhang M, Serna-Salas S, Damba T, Borghesan M, Demaria M, Moshage H . Hepatic stellate cell senescence in liver fibrosis: Characteristics, mechanisms and perspectives . Mechanisms of Ageing and Development . 199 . 111572 . October 2021 . 34536446 . 10.1016/j.mad.2021.111572 . 237524296 . free .
4. Valentijn FA, Falke LL, Nguyen TQ, Goldschmeding R . Cellular senescence in the aging and diseased kidney . Journal of Cell Communication and Signaling . 12 . 1 . 69–82 . March 2018 . 29260442 . 5842195 . 10.1007/s12079-017-0434-2 .
5. Elokdah H, Abou-Gharbia M, Hennan JK, McFarlane G, Mugford CP, Krishnamurthy G, Crandall DL . Tiplaxtinin, a novel, orally efficacious inhibitor of plasminogen activator inhibitor-1: design, synthesis, and preclinical characterization . Journal of Medicinal Chemistry . 47 . 14 . 3491–3494 . July 2004 . 15214776 . 10.1021/jm049766q . 10.1.1.661.4972 .
6. 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 . 6 . Characterization of the Annonaceous acetogenin, annonacinone, a natural product inhibitor of plasminogen activator inhibitor-1 . Scientific Reports . 6 . 36462 . November 2016 . 27876785 . 5120274 . 10.1038/srep36462 . 2016NatSR...636462P .
7. Boe AE, Eren M, Murphy SB, Kamide CE, Ichimura A, Terry D, McAnally D, Smith LH, Miyata T, Vaughan DE . 6 . Plasminogen activator inhibitor-1 antagonist TM5441 attenuates Nω-nitro-L-arginine methyl ester-induced hypertension and vascular senescence . Circulation . 128 . 21 . 2318–2324 . November 2013 . 24092817 . 3933362 . 10.1161/CIRCULATIONAHA.113.003192 .
8. Boncela J, Papiewska I, Fijalkowska I, Walkowiak B, Cierniewski CS . Acute phase protein alpha 1-acid glycoprotein interacts with plasminogen activator inhibitor type 1 and stabilizes its inhibitory activity . The Journal of Biological Chemistry . 276 . 38 . 35305–35311 . September 2001 . 11418606 . 10.1074/jbc.M104028200 . free .