Plasminogen activator inhibitor (PAI-1) has been isolated from many tissues, including liver, platelets, and endothelium. It inhibits t-PA (tissue plasminogen activator) and urokinase. PAI-1 is stored in the alpha-granules of platelets and is a single-chain glycoprotein with a molecular weight of 45,000 to 50,000 D. en
PAI-1 irreversibly binds covalently to t-PA and to urokinase. This slows down plasmin activation. PAI-1 is detectable in plasma in both bound and free forms. The free form is the biologically active one.
A further, clinically highly significant effect of PAI-1 was provided by arteriosclerosis research. It could be shown that an increased PAI-1 level is a biological risk factor for the development of arteriosclerosis and heart attacks.
Insulin resistance in visceral obesity has been shown to be associated with high plasma PAI-1 levels.
In primary focal segmental glomerulosclerosis, soluble plasminogen activator receptor is elevated (suPAR) in 65% of cases. This is associated with an increased tendency of the disease to recur.
Plasma PAI-1 levels are five times higher in obese animals than in non-obese animals. Experiments with homozygous PAI-1-deficient mice show much greater development of obesity under a high-calorie, high-fat diet than in PAI-1-positive animals. Thus, an increase in PAI-1 is a risk factor for the development of coronary heart disease. Weight loss and regular exercise can significantly lower elevated PAI-1 levels, thereby significantly reducing the risk of developing coronary sclerosis.
These influences of PAI-1, which lie beyond the actual clotting process, are currently the subject of atherosclerosis research. In addition, it has been observed that the effect of plasminogen activator inhibitor is important for tumor angiogenesis.
As a consequence of the antifibrinolytic effect of PAI-1, there is a reactive increase in t-PA concentration. PAI is elevated in thromboembolism, liver cirrhosis, tumors, polytrauma, sepsis, CHD, pregnancy and menopause. Ovulation inhibitors lower the PAI concentration. PAI-2 is a specific inhibitor of urokinase. The PAI-3 is identical to the protein Ca inactivator. The activity is determined with chromogenic substrates and is expressed in AU/ml. An AU inhibits an IE urokinase or an IE t-PA.
With the aid of an ELISA, the total concentration of PAI can be measured.
PAI is subject to multiple regulation. In particular, plasminogen activator inhibitor-1 is stimulated by endotoxin, cytokines, especially interleukin-1, tumor necrosis factor alpha, transforming growth factor beta, and hormones such as insulin and glocorticoids. In plasma, its concentration is 10-20ng/ml.
In addition, PAI-1 also affects cell adhesion and migration, mainly because of its influence on the urokinase plasminogen activator receptor. Likewise, it interferes with UPA receptor and vitronectin interactions as well as the process of cell adhesion by destroying intergrins and vitronectins.