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 PDB Ortholog search: PDBe RCSB List of PDB id codes 1A7C, 1B3K, 1C5G, 1DB2, 1DVM, 1DVN, 1LJ5, 1OC0, 3CVM, 3EOX, 3PB1, 3Q02, 3Q03, 3R4L, 3UT3, 4AQH, 4G8O, 4G8R, 4IC0, 9PAI, 5BRR,%%s1C5G
Identifiers
Aliases	SERPINE1, PAI, PAI-1, PAI1, PLANH1, serpin family E member 1
External IDs	OMIM: 173360; MGI: 97608; HomoloGene: 68070; GeneCards: SERPINE1; OMA:SERPINE1 - orthologs
Gene location (Human) Chr. Chromosome 7 (human)[1] Band 7q22.1 Start 101,127,104 bp[1] End 101,139,247 bp[1]
Gene location (Mouse) Chr. Chromosome 5 (mouse)[2] Band 5|5 G2 Start 137,090,358 bp[2] End 137,101,122 bp[2]
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in vena cava stromal cell of endometrium decidua saphenous vein ascending aorta gallbladder Descending thoracic aorta pericardium tibial arteries right coronary artery Top expressed in endothelial cell of lymphatic vessel stroma of bone marrow decidua tunica media of zone of aorta gastrula ascending aorta calvaria aortic valve muscle of thigh subcutaneous adipose tissue More reference expression data BioGPS More reference expression data
Gene ontology Molecular function peptidase inhibitor activity protease binding protein binding signaling receptor binding serine-type endopeptidase inhibitor activity Cellular component extracellular matrix plasma membrane extracellular exosome platelet alpha granule lumen extracellular region extracellular space collagen-containing extracellular matrix Biological process 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 signaling 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 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 by RNA polymerase II 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: 137.09 – 137.1 Mb PubMed search [3] [4]
Wikidata
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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

• 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.^[9]
• Annonacinone is a naturally occurring PAI-1 inhibitor found in plants of the Annonaceae family.^[10]
• TM5441 is another small molecule PAI-1 inhibitor used in research.^[11]

Interactions

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