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 SERPINE1gene. Elevated PAI-1 is a risk factor for
thrombosis and
atherosclerosis.[5]
The other PAI,
plasminogen activator inhibitor-2 (PAI-2) is secreted by the
placenta and only present in significant amounts during
pregnancy. In addition,
proteasenexin 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.
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 the synthesis of plasminogen activator inhibitor-1, so it accelerates the development of
atherosclerosis.
Mimuro J (May 1991). "[Type 1 plasminogen activator inhibitor: its role in biological reactions]". [Rinsho Ketsueki] the Japanese Journal of Clinical Hematology. 32 (5): 487–489.
PMID1870265.
Binder BR, Christ G, Gruber F, Grubic N, Hufnagl P, Krebs M, et al. (April 2002). "Plasminogen activator inhibitor 1: physiological and pathophysiological roles". News in Physiological Sciences. 17 (2): 56–61.
doi:
10.1152/nips.01369.2001.
PMID11909993.
S2CID21356023.
Eddy AA (August 2002). "Plasminogen activator inhibitor-1 and the kidney". American Journal of Physiology. Renal Physiology. 283 (2): F209–F220.
doi:
10.1152/ajprenal.00032.2002.
PMID12110504.
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): 1143–1149.
doi:
10.1515/BC.2002.125.
PMID12437099.
S2CID37813055.
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): 425–437.
doi:
10.1160/TH03-12-0764.
PMID14983217.
S2CID3898268.
Durand MK, Bødker JS, Christensen A, Dupont DM, Hansen M, Jensen JK, et al. (March 2004). "Plasminogen activator inhibitor-I and tumour growth, invasion, and metastasis". Thrombosis and Haemostasis. 91 (3): 438–449.
doi:
10.1160/TH03-12-0784.
PMID14983218.
S2CID3898546.
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): 450–456.
doi:
10.1160/TH03-12-0798.
PMID14983219.
S2CID19904733.
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.
PMID15090858.
S2CID30785986.
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): 861–872.
doi:
10.1160/TH03-08-0546.
PMID15116245.
S2CID21576955.
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): 149–154.
doi:
10.1016/j.coph.2005.01.007.
PMID15780823.
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): 631–640.
doi:
10.1160/TH05-01-0033.
PMID15841306.
S2CID8937106.
Könsgen D, Mustea A, Lichtenegger W, Sehouli J (June 2005). "[Role of PAI-1 in gynaecological malignancies]". Zentralblatt für Gynakologie. 127 (3): 125–131.
doi:
10.1055/s-2005-836407.
PMID15915389.
S2CID260353538.