Plasminogen activator inhibitor-1: a review Plasminogen-Aktivator-Inhibitor-1: eine Übersicht

Abstract

Abstract Plasminogen activator inhibitor-1 (PAI-1) is the most potent inhibitor of both tissue type (t-PA) and urokinase type plasminogen activator (u-PA) and thus regulates fibrinolysis as well as proteolysis, cell migration, and tumor cell invasiveness. Stimulated by cytokines, lipopolysaccharide, very low density lipoproteins, and transforming growth factor β-1 (TGF β-1), PAI-1 also influences inflammation, metabolic disorders, and fibrotic diseases. PAI-1 is produced in liver cells, adipocytes, smooth muscle cells, and platelets. In pathological conditions, increased PAI-1 levels mainly result from release by endothelial cells or tumor cells. Elevation of PAI-1 activity is described to be associated with pregnancy complications like recurrent miscarriage, pregnancy-induced hypertension, and preeclampsia. Spontaneous abortion seems to be related to the 4G/4G genotype of the polymorphism in the PAI-1 promoter. Women with polycystic ovarian syndrome, which is associated with anovulatory infertility, also show significantly higher PAI-1 levels than healthy controls. Increased PAI-1 levels are found in a number of malignancies and might give information about prognosis and preferential response to certain therapies especially in patients with primary breast cancer. By influencing extracellular matrix turnover, PAI-1 seems to play a role in fibrotic disorders including nephropathy, chronic lung diseases, cardiac fibrosis, and liver fibrosis. Upregulated by inflammatory mediators, PAI-1 levels are increased in sepsis, trauma, surgery, and a variety of diseases associated with inflammatory reactions. PAI-1 is suggested to play a functional role in host response to trauma. Inflammatory states are also found in the pathogenesis of atherosclerosis and the metabolic syndrome. Vascular diseases as well as insulin resistance leading to metabolic state are associated with both elevated PAI-1 levels and the 4G/5G polymorphism of the PAI-1 promoter. The 4G/4G and 4G/5G genotypes were observed to be more frequent in patients with obesity, myocardial infarction, and venous thromboembolism. PAI-1 thus represents an important non-invasive diagnostic criterion in a number of diseases and might reveal new therapeutic strategies.