Plasminogen activator inhibitor-1

Plasminogen activator inhibitor-1 (PAI-1) also known as endothelial plasminogen activator inhibitor or serpin E1 is a is_associated_with::protein that in humans is encoded by the SERPINE1 is_associated_with::gene. Elevated PAI-1 is a risk factor for is_associated_with::thrombosis and is_associated_with::atherosclerosis

PAI-1 is a serine protease inhibitor (is_associated_with::serpin) that functions as the principal inhibitor of is_associated_with::tissue plasminogen activator (tPA) and is_associated_with::urokinase (uPA), the activators of is_associated_with::plasminogen and hence is_associated_with::fibrinolysis (the physiological breakdown of blood clots). It is a is_associated_with::serine protease inhibitor (serpin) protein (SERPINE1).

The other PAI, is_associated_with::plasminogen activator inhibitor-2 (PAI-2) is secreted by the is_associated_with::placenta and only present in significant amounts during is_associated_with::pregnancy. In addition, is_associated_with::protease is_associated_with::nexin acts as an inhibitor of tPA and urokinase. PAI-1, however, is the main inhibitor of the plasminogen activators.

Genetics
The PAI-1 is_associated_with::gene is SERPINE1, located on is_associated_with::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 is mainly produced by the is_associated_with::endothelium (cells lining is_associated_with::blood vessels), but is also secreted by other tissue types, such as is_associated_with::adipose tissue.

PAI-1 inhibits the is_associated_with::serine proteases tPA and uPA/urokinase, and hence is an inhibitor of is_associated_with::fibrinolysis, the physiological process that degrades blood clots.

PAI-1 inhibits the activity of matrix metalloproteinases, which play a crucial role in invasion of malignant cells across the is_associated_with::basal lamina.



Role in disease
Congenital deficiency of PAI-1 has been reported; as fibrinolysis is not suppressed adequately, it leads to a is_associated_with::hemorrhagic diathesis (a tendency to hemorrhage).

PAI-1 is present in increased levels in various disease states (such as a number of forms of is_associated_with::cancer), as well as in is_associated_with::obesity and the is_associated_with::metabolic syndrome. It has been linked to the increased occurrence of is_associated_with::thrombosis in patients with these conditions.

In inflammatory conditions in which is_associated_with::fibrin is deposited in tissues, PAI-1 appears to play a significant role in the progression to is_associated_with::fibrosis (pathological formation of is_associated_with::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 is_associated_with::atherosclerosis.

Pharmacology
is_associated_with::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 is_associated_with::arterial hypertension and activation of the is_associated_with::renin-angiotensin system.

Interactions
Plasminogen activator inhibitor-1 has been shown to interact with is_associated_with::ORM1.