Plasminogen activator inhibitor-1

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.[5]

SERPINE1
Available structures
PDBOrtholog search: PDBe RCSB
Identifiers
AliasesSERPINE1, PAI, PAI-1, PAI1, PLANH1, serpin family E member 1
External IDsOMIM: 173360 MGI: 97608 HomoloGene: 68070 GeneCards: SERPINE1
Orthologs
SpeciesHumanMouse
Entrez

5054

18787

Ensembl

ENSG00000106366

ENSMUSG00000037411

UniProt

P05121

P22777

RefSeq (mRNA)

NM_001165413
NM_000602

NM_008871

RefSeq (protein)

NP_000593
NP_000593.1

NP_032897

Location (UCSC)Chr 7: 101.13 – 101.14 MbChr 5: 137.09 – 137.1 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

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.[6] 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.

Fibrinolysis (simplified). Blue arrows denote stimulation, and red arrows inhibition.

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.[7] PAI-1 can also be a component of the senescence-associated secretory phenotype (SASP).[8]

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

Interactions

Plasminogen activator inhibitor-1 has been shown to interact with ORM1.[12]

References

  1. GRCh38: Ensembl release 89: ENSG00000106366 - Ensembl, May 2017
  2. GRCm38: Ensembl release 89: ENSMUSG00000037411 - Ensembl, May 2017
  3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. Vaughan DE (August 2005). "PAI-1 and atherothrombosis". Journal of Thrombosis and Haemostasis. 3 (8): 1879–1883. doi:10.1111/j.1538-7836.2005.01420.x. PMID 16102055. S2CID 6651339.
  6. Carter JC, Church FC (2009). "Obesity and breast cancer: the roles of peroxisome proliferator-activated receptor-γ and plasminogen activator inhibitor-1". PPAR Research. 2009: 345320. doi:10.1155/2009/345320. PMC 2723729. PMID 19672469.
  7. Zhang M, Serna-Salas S, Damba T, Borghesan M, Demaria M, Moshage H (October 2021). "Hepatic stellate cell senescence in liver fibrosis: Characteristics, mechanisms and perspectives". Mechanisms of Ageing and Development. 199: 111572. doi:10.1016/j.mad.2021.111572. PMID 34536446. S2CID 237524296.
  8. Valentijn FA, Falke LL, Nguyen TQ, Goldschmeding R (March 2018). "Cellular senescence in the aging and diseased kidney". Journal of Cell Communication and Signaling. 12 (1): 69–82. doi:10.1007/s12079-017-0434-2. PMC 5842195. PMID 29260442.
  9. Elokdah H, Abou-Gharbia M, Hennan JK, McFarlane G, Mugford CP, Krishnamurthy G, Crandall DL (July 2004). "Tiplaxtinin, a novel, orally efficacious inhibitor of plasminogen activator inhibitor-1: design, synthesis, and preclinical characterization". Journal of Medicinal Chemistry. 47 (14): 3491–3494. CiteSeerX 10.1.1.661.4972. doi:10.1021/jm049766q. PMID 15214776.
  10. Pautus S, Alami M, Adam F, Bernadat G, Lawrence DA, De Carvalho A, et al. (November 2016). "Characterization of the Annonaceous acetogenin, annonacinone, a natural product inhibitor of plasminogen activator inhibitor-1". Scientific Reports. 6: 36462. Bibcode:2016NatSR...636462P. doi:10.1038/srep36462. PMC 5120274. PMID 27876785.
  11. Boe AE, Eren M, Murphy SB, Kamide CE, Ichimura A, Terry D, et al. (November 2013). "Plasminogen activator inhibitor-1 antagonist TM5441 attenuates Nω-nitro-L-arginine methyl ester-induced hypertension and vascular senescence". Circulation. 128 (21): 2318–2324. doi:10.1161/CIRCULATIONAHA.113.003192. PMC 3933362. PMID 24092817.
  12. Boncela J, Papiewska I, Fijalkowska I, Walkowiak B, Cierniewski CS (September 2001). "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. doi:10.1074/jbc.M104028200. PMID 11418606.

Further reading

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