limit, block, or decrease the action or function of; "inhibit the action of the enzyme"; "inhibit the rate of a chemical reaction"
control and refrain from showing; of emotions, desires, impulses, or behavior (同)bottle up, suppress
limit the range or extent of; "Contact between the young was inhibited by strict social customs"
a substance that retards or stops an activity
(biology) any agency bringing about activation; a molecule that increases the activity of an enzyme or a protein that increases the production of a gene product in DNA transcription
an inactive form of plasmin that occurs in plasma and is converted to plasmin by organic solvents
• negative regulation of endothelial cell apoptotic process • positive regulation of receptor-mediated endocytosis • negative regulation of peptidase activity • negative regulation of fibrinolysis • positive regulation of inflammatory response • negative regulation of plasminogen activation • fibrinolysis • negative regulation of smooth muscle cell-matrix adhesion • negative regulation of blood coagulation • negative regulation of vascular wound healing • regulation of receptor activity • negative regulation of smooth muscle cell migration • positive regulation of monocyte chemotaxis • platelet degranulation • extracellular matrix organization • positive regulation of angiogenesis • negative regulation of cell migration • chronological cell aging • positive regulation of blood coagulation • defense response to Gram-negative bacterium • negative regulation of extrinsic apoptotic signaling pathway via death domain receptors • circadian rhythm • angiogenesis • positive regulation of interleukin-8 production • negative regulation of wound healing • cellular response to lipopolysaccharide • negative regulation of cell adhesion mediated by integrin • negative regulation of endopeptidase activity • positive regulation of transcription from RNA polymerase II promoter • positive regulation of leukotriene production involved in inflammatory response • replicative senescence • dentinogenesis • positive regulation of odontoblast differentiation
Sources:Amigo / QuickGO
Orthologs
Species
Human
Mouse
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 Mb
Chr 5: 137.06 – 137.07 Mb
PubMed search
[3]
[4]
Wikidata
View/Edit Human
View/Edit Mouse
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. Elevated PAI-1 is a risk factor for thrombosis and atherosclerosis[5]
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.
Contents
1Genetics
2Function
3Role in disease
4Pharmacology
5Interactions
6References
7Further reading
8External links
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.
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
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.[7]
Annonacinone is a naturally occurring PAI-1 inhibitor found in plants of the Annonaceae family.[8]
Interactions
Plasminogen activator inhibitor-1 has been shown to interact with ORM1.[9]
References
^ abcGRCh38: Ensembl release 89: ENSG00000106366 - Ensembl, May 2017
^ abcGRCm38: Ensembl release 89: ENSMUSG00000037411 - Ensembl, May 2017
^"Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
^"Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
^Vaughan DE (August 2005). "PAI-1 and atherothrombosis". Journal of Thrombosis and Haemostasis. 3 (8): 1879–83. doi:10.1111/j.1538-7836.2005.01420.x. PMID 16102055.
^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.
^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): 3491–4. CiteSeerX 10.1.1.661.4972. doi:10.1021/jm049766q. PMID 15214776.
^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 (2016). "Characterization of the Annonaceous acetogenin, annonacinone, a natural product inhibitor of plasminogen activator inhibitor-1". Scientific Reports. 6: 36462. doi:10.1038/srep36462. PMC 5120274. PMID 27876785.
^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): 35305–11. doi:10.1074/jbc.M104028200. PMID 11418606.
Further reading
Mimuro J (May 1991). "[Type 1 plasminogen activator inhibitor: its role in biological reactions]". [Rinshō Ketsueki] the Japanese Journal of Clinical Hematology. 32 (5): 487–9. PMID 1870265.
Binder BR, Christ G, Gruber F, Grubic N, Hufnagl P, Krebs M, Mihaly J, Prager GW (April 2002). "Plasminogen activator inhibitor 1: physiological and pathophysiological roles". News in Physiological Sciences. 17: 56–61. PMID 11909993.
Eddy AA (August 2002). "Plasminogen activator inhibitor-1 and the kidney". American Journal of Physiology. Renal Physiology. 283 (2): F209–20. doi:10.1152/ajprenal.00032.2002. PMID 12110504.
Wang J, Li J, Liu Q (August 2005). "Association between platelet activation and fibrinolysis in acute stroke patients". Neurosci. Lett. 384 (3): 305–9. doi:10.1016/j.neulet.2005.04.090. PMID 15916851.
Schroeck F, Arroyo de Prada N, Sperl S, Schmitt M, Viktor M (2003). "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): 1143–9. doi:10.1515/BC.2002.125. PMID 12437099.
Gils A, Declerck PJ (March 2004). "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): 425–37. doi:10.1160/TH03-12-0764. PMID 14983217.
Durand MK, Bødker JS, Christensen A, Dupont DM, Hansen M, Jensen JK, Kjelgaard S, Mathiasen L, Pedersen KE, Skeldal S, Wind T, Andreasen PA (March 2004). "Plasminogen activator inhibitor-I and tumour growth, invasion, and metastasis". Thrombosis and Haemostasis. 91 (3): 438–49. doi:10.1160/TH03-12-0784. PMID 14983218.
Harbeck N, Kates RE, Gauger K, Willems A, Kiechle M, Magdolen V, Schmitt M (March 2004). "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): 450–6. doi:10.1160/TH03-12-0798. PMID 14983219.
Hertig A, Rondeau E (January 2004). "Plasminogen activator inhibitor type 1: the two faces of the same coin". Current Opinion in Nephrology and Hypertension. 13 (1): 39–44. doi:10.1097/00041552-200401000-00006. PMID 15090858.
Hoekstra T, Geleijnse JM, Schouten EG, Kluft C (May 2004). "Plasminogen activator inhibitor-type 1: its plasma determinants and relation with cardiovascular risk". Thrombosis and Haemostasis. 91 (5): 861–72. doi:10.1160/TH03-08-0546. PMID 15116245.
Lijnen HR (January 2005). "Pleiotropic functions of plasminogen activator inhibitor-1". Journal of Thrombosis and Haemostasis. 3 (1): 35–45. doi:10.1111/j.1538-7836.2004.00827.x. PMID 15634264.
De Taeye B, Smith LH, Vaughan DE (April 2005). "Plasminogen activator inhibitor-1: a common denominator in obesity, diabetes and cardiovascular disease". Current Opinion in Pharmacology. 5 (2): 149–54. doi:10.1016/j.coph.2005.01.007. PMID 15780823.
Dellas C, Loskutoff DJ (April 2005). "Historical analysis of PAI-1 from its discovery to its potential role in cell motility and disease". Thrombosis and Haemostasis. 93 (4): 631–40. doi:10.1160/TH05-01-0033. PMID 15841306.
Könsgen D, Mustea A, Lichtenegger W, Sehouli J (June 2005). "[Role of PAI-1 in gynaecological malignancies]". Zentralblatt für Gynäkologie. 127 (3): 125–31. doi:10.1055/s-2005-836407. PMID 15915389.
Hermans PW, Hazelzet JA (November 2005). "Plasminogen activator inhibitor type 1 gene polymorphism and sepsis". Clinical Infectious Diseases. 41 Suppl 7: S453–8. doi:10.1086/431996. PMID 16237647.
Alessi MC, Poggi M, Juhan-Vague I (June 2007). "Plasminogen activator inhibitor-1, adipose tissue and insulin resistance". Current Opinion in Lipidology. 18 (3): 240–5. doi:10.1097/MOL.0b013e32814e6d29. PMID 17495595.
External links
The MEROPS online database for peptidases and their inhibitors: I04.020
Plasminogen+Activator+Inhibitor+1 at the US National Library of Medicine Medical Subject Headings (MeSH)
Overview of all the structural information available in the PDB for UniProt: P05121 (Plasminogen activator inhibitor 1) at the PDBe-KB.
v
t
e
PDB gallery
1a7c: HUMAN PLASMINOGEN ACTIVATOR INHIBITOR TYPE-1 IN COMPLEX WITH A PENTAPEPTIDE
1b3k: Plasminogen activator inhibitor-1
1c5g: PLASMINOGEN ACTIVATOR INHIBITOR-1
1db2: CRYSTAL STRUCTURE OF NATIVE PLASMINOGEN ACTIVATOR INHIBITOR-1
1dvm: ACTIVE FORM OF HUMAN PAI-1
1dvn: LATENT FORM OF PLASMINOGEN ACTIVATOR INHIBITOR-1 (PAI-1)
1lj5: 1.8A Resolution Structure of Latent Plasminogen Activator Inhibitor-1(PAI-1)
1oc0: PLASMINOGEN ACTIVATOR INHIBITOR-1 COMPLEX WITH SOMATOMEDIN B DOMAIN OF VITRONECTIN
9pai: CLEAVED SUBSTRATE VARIANT OF PLASMINOGEN ACTIVATOR INHIBITOR-1
v
t
e
Proteins involved in coagulation
Coagulation factors
Primary hemostasis
vWF
platelet membrane glycoproteins: Ib (A
B
IX)
IIb/IIIa (IIb
IIIa)
VI
Intrinsic pathway
HMWK/Bradykinin
Prekallikrein/Kallikrein
XII "Hageman"
XI
IX
VIII
Extrinsic pathway
III "Tissue factor"
VII
Common pathway
X
V
II "(Pro)thrombin"
I "Fibrin"
Fibrinogen (FGA, FGG)
XIII
Coagulation inhibitors
Antithrombin (inhibits II, IX, X, XI, XII)
Protein C (inhibits V, VIII)/Protein S (cofactor for protein C)
Protein Z (inhibits X)
ZPI (inhibits X, XI)
TFPI (inhibits III)
Thrombolysis/fibrinolysis
Plasmin
tPA/urokinase
PAI-1/2
α2-AP
α2-macroglobulin
TAFI
v
t
e
Serpins
inhibitory
Alpha 1-antichymotrypsin
Alpha 1-antitrypsin
Alpha 2-antiplasmin
Antithrombin
C1-inhibitor
Heparin cofactor II
Protein C inhibitor
Plasminogen activator inhibitor-1
Plasminogen activator inhibitor-2
Protein Z-related protease inhibitor
SERPINA1
SERPINA2
SERPINA3
SERPINA4
SERPINA5
SERPINA9
SERPINA14
SERPINB1
SERPINB2
SERPINB3
SERPINB4
SERPINB5
SERPINB6
SERPINB7
SERPINB8
SERPINB9
SERPINB13
SERPINC1
SERPIND1
SERPINE1
SERPINE2
SERPINE2
SERPINF1
SERPING1
SERPINH1
SERPINI1
SERPINI2
Cross class inhibitory
MENT
SCCA-1
CrmA
noninhibitory
Heat shock protein 47
Maspin
Ovalbumin
SERPINF1
Transcortin
Thyroxine-binding globulin
Angiotensinogen
SERPINF1
see also disorders of globin and globulin proteins
UpToDate Contents
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…individuals with this disorder. Plasminogen activator inhibitor-1 (PAI-1) deficiency is a rare cause of abnormal bleeding . Two studies reported a kindred with complete PAI-1 deficiency due to a small insertion …
…of the methylenetetrahydrofolate reductase (MTHFR) 677C—>T, MTHFR 1298 A—>C, or plasminogen activator inhibitor-1 (PAI-1) 4G/5G promoter variants in asymptomatic individuals, and we never order these tests…
…(tissue-type plasminogen activator and urokinase-type plasminogen activator) and plasminogen activator inhibitors (PAI-1 and PAI-2). The tPA molecule is predominantly an endothelial cell enzyme. Its release …
…the deep veins of the legs, thereby preventing venous stasis . IPC also reduces plasminogen activator inhibitor-1 (PAI-1), thereby increasing endogenous fibrinolytic activity . IPC devices are an alternative…
English Journal
Pirfenidone inhibits motility of NSCLC cells by interfering with the urokinase system.
Krämer M, Markart P, Drakopanagiotakis F, Mamazhakypov A, Schaefer L, Didiasova M, Wygrecka M.
Cellular signalling. 2020 Jan;65()109432.
Pirfenidone (PFD) is an orally available synthetic drug which has been approved for the treatment of idiopathic pulmonary fibrosis. In addition to its anti-fibrotic properties, PFD also exerts anti-tumor effects in cancer models by inducing alterations in the tumor microenvironment. Here, we demonst
PAI-1 contributes to homocysteine-induced cellular senescence.
Sun T, Ghosh AK, Eren M, Miyata T, Vaughan DE.
Cellular signalling. 2019 Dec;64()109394.
Cellular Senescence is associated with organismal aging and related pathologies. Previously, we reported that plasminogen activator inhibitor-1 (PAI-1) is an essential mediator of senescence and a potential therapeutic target for preventing aging-related pathologies. In this study, we investigate th
Upregulated MiR-9-5p Protects Against Inflammatory Response in Rats with Deep Vein Thrombosis via Inhibition of NF-κB p50.
Ou M, Zhang Y, Cui S, Zhao S, Tu J.
Inflammation. 2019 Dec;42(6)1925-1938.
Recently, microRNAs (miRNAs) have been demonstrated to play important roles in the cardiovascular system, including heart, blood vessels, plasma, and vascular diseases. Deep vein thrombosis (DVT) refers to the formation of blood clot in the deep veins of the human body and is a common peripheral vas
Nuclear factor erythroid 2-related factor 2 (NRF2) is a negative regulator of tissue plasminogenactivator synthesis in cultured human vascular endothelial EA.hy926 cells
… Fibrinolysis in normal circulating blood strongly depends on the balance between tissue-type plasminogenactivator (t-PA) and plasminogenactivatorinhibitor-1 (PAI-1) secreted from vascular endothelial cells; …
Impact of Serum Adiponectin, PlasminogenActivatorInhibitor-1, and Oxidative Stress Levels on Eosinophilic Inflammation of the Airway and the Whole Body in Children with Obesity
… Adiponectin was significantly lower in the high FENO group than in the normal FENO group (6.5 vs. 8.1 μg/mL, p<0.02). … A negative correlation between B-Eos count values and adiponectin levels (r=−0.34, p<0.05) and a positive correlation between B-Eos count values and plasminogenactivatorinhibitor-1 levels were noted (r=0.42, p<0.01). …
Fibrinolytic Activity of Circulating Microvesicles Is Associated with Progression of Breast Cancer
Valente-Acosta Benjamín,Flores-García Mirthala,González-Zárate Georgina,Gerson-Cwilich Raquel,Maldonado-Méndez Marai,Juárez-Vega Guillermo,Anglés-Cano Eduardo,Peña-Díaz Aurora de la
The Tohoku Journal of Experimental Medicine 250(2), 121-128, 2020
… The expression of urokinase-type plasminogenactivator (uPA) in breast cancer tissue is widely recognized as an unfavorable prognostic factor. … However, fibrinolytic activity associated with uPA cannot be reliably measured in the blood because of the rapid inhibition of uPA by plasminogenactivatorinhibitor-1 (PAI-1). …
Soeda S, Shinomiya K, Ochiai T, et al. Plasminogen activator inhibitor-1 aids nerve growth factor-induced differentiation and survival of pheochromocytoma cells by activating both the extracellular signal-regulated kinase and c-Jun
PAI1 : Plasminogen activator inhibitor type 1 (PAI-1) antigen is a single-chain glycoprotein (MW 50,000) produced by endothelial cells and hepatocytes and is also present in alpha granules of platelets. PAI-1 is a serine protein ...
