A Role for Plasminogen Activator Inhibitor-1 in Obesity: From Pie to PAI?

Abstract

The regulation of fibrinolysis depends on the interaction of plasma fibrinolytic and anti-fibrinolytic proteins. Fibrinolysis depends on the enzymatic conversion of plasminogen to plasmin. This process is mediated by tissue-type and urokinase-type plasminogen activators (t & uPAs, respectively). See page 2209 Plasma antifibrinolytic activity is primarily regulated by plasminogen-activator inhibitors (PAIs).1 Four PAIs have been described: PAIs-1 through 3 and protease nexin. Importantly, PAI-1 is the main antagonist of t & uPAs, accounting for approximately 60% of the inhibition of plasminogen activators. PAI-2 mostly inhibits urokinase plasminogen activator (uPA), whereas protease nexin antagonizes plasmin, thrombin, and uPA. The antifibrinolytic activity of PAI-3 is uncertain. These molecules and others are also collectively known as serine protease inhibitors or “serpins”. PAI-1 is a single chain 45-kDa glycoprotein that contains from 379 to 381 amino acids. Endothelial and vascular smooth muscle cells are presumably the main sources of PAI-1 but other cells, such as platelets, hepatocytes, mesangial cells, fibroblasts, monocytes, macrophages, adipocytes, and stromal cells permeating the adipose tissue, have also been shown to secrete the serpin. The gene for PAI-1 is located on chromosome 7q21.3-q22, and its expression is mainly regulated at the transcriptional level through the action of several hormones [eg, renin-angiotensin-aldostrerone system (RAAS)], cytokines [eg, tumor necrosis factor (TNF) α], lipoproteins (eg, VLDL), glucose, and endotoxin.1 Polymorphisms that influence PAI-1 gene expression have been described. The single 4/5 guanine polymorphism (4G/5G) in the promoter region of PAI-1 gene is widespread and has been associated with variable plasma PAI-1 activity and antigen levels.1 Indeed, plasma expression of PAI-1 antigen and activity are augmented in homozygous subjects for the 4G allele but decreased in 5G allele homozygous. This polymorphism may have important implications for human cardiovascular disease as suggested by case–control studies showing a higher prevalence of the 4G …